Use of Exendins and Agonists Thereof for the Treatment of Gestational Diabetes Mellitus

ABSTRACT

Methods for treating gestational diabetes which comprise administration of an effective amount of an exendin or an exendin agonist, alone or in conjunction with other compounds or compositions that lower blood glucose levels.

RELATED APPLICATIONS

This application is a continuation of co-pending U.S. application Ser.No. 10/342,014, filed on Jan. 13, 2003, which is a continuationApplication of U.S. application Ser. No. 09/323,867, filed on Jun. 1,1999, now U.S. Pat. No. 6,506,724.

INCORPORATION OF SEQUENCE LISTING

A paper copy of the Sequence Listing and a computer readable form of thesequence listing on diskette, containing the file named Seq.txt, whichcan be found in co-pending U.S. application Ser. No. 10/342,014 andwhich was created on May 7, 2003, are herein incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to methods for treating gestationaldiabetes mellitus comprising administration of an effective amount of anexendin or an exendin agonist alone or in conjunction with othercompounds or compositions that affect blood glucose control, such as aninsulin or an amylin agonist. Pharmaceutical compositions for use in themethods of the invention are also disclosed.

BACKGROUND

The following description summarizes information relevant to the presentinvention. It is not an admission that any of the information providedherein is prior art to the presently claimed invention, nor that any ofthe publications specifically or implicitly referenced are prior art tothat invention.

Gestational Diabetes Mellitus

Gestational diabetes mellitus (“GDM”) is a disorder associated withelevated circulating plasma glucose. Although the diagnostic criteriafor GDM have been the subject of controversy for decades, it was definedby the Third Workshop Conference on Gestational Diabetes Mellitus ascarbohydrate intolerance of varying severity with onset or firstrecognition during pregnancy, irrespective of the glycemic status afterdelivery. Metzger (ed.) Proceedings of the Third International WorkshopConference on Gestational Diabetes Mellitus, Diabetes 40(Suppl. 2),1991. Despite advances in clinical management of GDM, there are problemsassociated with GDM which persist, including elevated rate of perinatalmorbidity and elevated rate of malformations in newborns. Persson etal., Diabetes and Pregnancy, In International Textbook of DiabetesMellitus, Second Edition, John Wiley & Sons 1997 (Alberti et al. Eds.).For example, it has been reported that, when the mean blood glucoselevel is greater than 105 mg/dl, there is a greater risk for thedevelopment of large-for-gestational age (“LGA”) infants when comparedwith a control population. Id. Additional reported consequences ofuntreated GDM include an increased incidence of macrosomia, respiratorydistress syndrome, and other abnormalities of fetal metabolism. Langer,Am. J. Obstet. Gynecol. 176:S186, 1997; American Diabetes Association:Self-Monitoring of Blood Glucose Consensus Statement, Diabetes Care17:81-82, 1994 (“ABA Consensus Statement”); Coetzee & Jackson, S. Afr.Med. J. 56:467-475, 1979. It has been clearly established by those inthe field that tight glycemic control can serve as the primaryprevention of fetal disease relating to GDM. Drexel et al., DiabetesCare 11:761-768, 1988; Roversi et al., Diabetes Care 3:489-494, 1980;Langer & Mazze, Am. J. Obstet. Gynecol. 159:1478-1483, 1988; Langer etal., Am. J. Obstet. Gynecol. 161:646-653, 1989). GDM results in agreater incidence of intrauterine death or neonatal mortality. PositionStatement American Diabetes Association Gestational Diabetes Mellitus,Diabetes Care 21 (Suppl. 1):S60-61, 1998. GDM pregnancies are at anincreased risk for fetal macrosomia and neonatal morbidities includingneural tube defects, hypoglycemia, hypocalcemiea, hypomagnsemia,polycythemia and hyperbilirubinemia and subsequent childhood andadolescent obesity. Siccardi, Gestational Diabetes. Other complicationsto the woman include increased rates of cesarean delivery, hypertensivedisorders including preeclamsia and urinary tract infections.

It has been reported that approximately 4% of all pregnancies (135,000cases annually) are complicated by GDM, however, it has been estimatedthat the incidence may range from 1% to 14% of all pregnancies,depending on the population and diagnostic tests employed. ADA ConsensusStatement, supra.

Normally during pregnancy, fasting plasma levels of insulin graduallyincrease to reach concentrations that are approximately twice as high inthe third trimester as they were outside of pregnancy. Women withgestational diabetes mellitus (“GDM”) have fasting insulin levelscomparable to or higher than those of normal pregnant women with thehighest levels seen in women with GDM who are obese. Insulin secretionalso increases gradually in pregnancy and also reaches a maximum duringthe third trimester. However, the relative increase in secretion issignificantly smaller in women with GDM than in normal glucose tolerant(“NGT”) women. The first-phase insulin response in NGT women issignificantly higher than in GDM women; second phase insulin responsewas similarly increased during pregnancy in both groups. This finding isconsistent with the finding that GDM women have a later time of peakinsulin concentration during an oral glucose tolerance test than do NGTwomen. Consistent with this observation, the insulin response per unitof glycemic stimulus is significantly higher in NGT women than in GDMwomen (90% and 40%, respectively). The fact that glucose tolerancedeteriorates in both normal and GDM pregnancies while at the same time,insulin secretion increases indicates a decrease in insulin sensitivity.Comparative results from an intravenous glucose tolerance test and ahyperinsulinemic, euglycemic clamp showed a sensitivity decrease duringpregnancy in both groups of 50-60%, but GDM women had a slightly lowersensitivity. In another study using radioactive glucose, turnover ofglucose and amino acids in GDM women was comparable to NGT women onlywhen insulin concentrations 3-5 fold higher in the GDM group were used.Thus, it appears that GDM is due to a combination of diminished insulinsensitivity and an impaired ability to increase insulin secretion andhas, in fact, many features in common with type 2 diabetes. Normal ornear normal glycemic control returns upon parturition.

Clinical Diagnosis

It is common clinical practice to screen women for elevated glucose andglucose intolerance between weeks 24 and 28 of gestation, especiallywomen with any one the following four characteristics: age≧25;race/ethnicity of Hispanic, Native American, Asian, African-American orPacific Islander origin; obese or a family history of diabetes. Inaddition, women with previous pregnancies with complications due to alarge weight fetus/neonate are usually tested. In some medical centersall pregnant women are tested. Indeed, certain investigators have foundthat historical risk factors account for only roughly half of the womenknown to have GDM. Carr, Diabetes Care 21(Suppl. 2):B14-B18, 1998.Additionally, there is some reported evidence that advancing maternalage is associated with increased incidence of GDM. Id.

The clinical diagnosis is generally based on a multi-step process. Theevaluation is most typically performed by measuring plasma glucose 1hour after a 50-gram oral glucose challenge test in either the fasted orthe unfasted state. If the value in the glucose challenge test is ≧140mg/dl, a 3-hr 100 g oral glucose tolerance test is done. If two or moreof the following criteria are met, the patient is considered in need ofglycemic control: fasted venous plasma≧105 mg/dl, venous plasma≧190mg/dl at 1 hr, venous plasma≧165 mg/dl at 2 hr or venous plasma≧145mg/dl at 3 hr. Williams et al., Diabetes Care 22: 418-421, 1999.Variations of this test are also used by some. See, e.g., Coustan,Gestational Diabetes In Diabetes in America, 2d ed. National Institutesof Health Publication No. 95-1468, 1995.

Current Clinical Therapy

The current therapeutic approach for GDM is to control plasma glucosefor the remainder of the gestation (i.e., the third trimester throughparturition). GDM has many features in common with type 2 diabetes. Theendocrine (impaired insulin secretion) and metabolic (insulinresistance) abnormalities that characterize both forms of diabetes aresimilar. In general, pregnancy is characterized by increases in bothinsulin resistance and insulin secretion. Women with GDM fail to respondwith increased insulin to the decrease in insulin sensitivity.

A significant correlation has been shown to exist between late-stagegestational maternal glucose levels and preeclamsia, macrosomia,Cesarean section delivery and phototherapy for hyperbilirubinemia.Sermer et al., Diabetic Care 21 (Suppl. 2):B33-B42, 1998. It has alsobeen determined that the length of hospitalization of the new mother andthe length of time the neonate spent in the nursery could be correlatedto the degree of elevation of plasma glucose in the pregnant woman. Id.Tallarigo, et al. reported a striking rise in the risk of fetalmacrosomia (9.9 vs. 27.5%) and preeclamsia/Cesarean sections (19.9 vs.40.0%) in women with abnormal glucose tolerance when compared to NGTwomen. Tallarigo et al., N. Engl. J. Med. 315:989-992, 1986.

Thus, the goals for therapy of GDM are to achieve and maintain as nearnormal glycemia as feasible with a special emphasis to keep postprandialglucose concentrations within the normal range. Optimal therapeuticstrategies are safe and efficacious in achieving a metabolic balancingwithout creating complications, which may include ketosis and/orhypoglycemia. Jovanovic, Diabetes Care 21(Suppl. 2):B131-B137, 1998. Theinitial therapeutic approach is through diet. Jovanovic-Peterson &Peterson, J. Am. Coll. Nutr. 9:320-325, 1990.

If diet or diet and exercise are not effective (i.e., failure is fastingglucose≧105 mg/dl and/or a 2-hr postprandial plasma glucose of ≧120mg/dl on 2 or more occasions within a 1- to 2-week period), then insulintherapy (preferably, human insulin) is considered appropriate. ADAPosition Statement, supra.

Oral glucose-lowering agents are not recommended during pregnancy. Kuhlet al., Diabetic Care 21 (Suppl. 2): B19-B26, 1998. Althoughsulfonylureas are used in the treatment of type 2 diabetes due to theiractivity in increasing insulin sensitivity, these agents arecontraindicated for use in GDM. Jovanovic, Diabetes Care 21 (Suppl.2):B131-B137, 1998. See also Kahn & Shechter, Insulin, Oral HypoglycemicAgents, and the Pharmacology of the Endocrine Pancreas, In Goodman &Gilman's The Pharmacological Basis of Therapeutics (8^(th) ed. 1993Goodman Gilman et al. eds.). Oral hypoglycemic drugs traverse theplacenta, and may cause prolonged severe hypoglycemia in the newborn.Persson et al., supra.

The difficulties with, and the highly variable approaches to insulintherapy in GDM have been reviewed, for example, by Langer, et al.Langer, Diabetes Care 21(Suppl. 2):B91-B98, 1998. The problems commonlyassociated with insulin therapy in a non-pregnant population remain whenused in the treatment of GDM. They are determination of the proper dose,maintenance of good glucose control through each 24-hr period, possiblehypoglycemia and weight gain. Hypoglycemia can result when insulin isadministered to control postprandial plasma glucose, but the fetusdemands for energy in the presence of excess insulin later causes theglucose level to drop to a hypoglycemic level. This physiological statecan be dangerous to both the mother and the fetus. Excess weight gain isundesirable in any pregnancy. Another problem with insulin therapy isthe day-to-day and week-to-week variability in glucose control vs.insulin dose.

Thus, it can be appreciated that an effective means to treat gestationaldiabetes remains a major challenge and a superior method of treatmentwould be of great utility. Such a method, and compounds and compositionswhich are useful therefor, have been invented and are described andclaimed herein.

Exendins and Exendin Agonists

Exendins are peptides that were first isolated from the salivarysecretions of the Gila-monster, a lizard found in Arizona, and theMexican Beaded Lizard. Exendin-3 is present in the salivary secretionsof Heloderma horridum, and exendin-4 is present in the salivarysecretions of Heloderma suspectum (Eng, J., et al., J. Biol. Chem.,265:20259-62, 1990; Eng., J., et al., J. Biol. Chem., 267:7402-05,1992). The exendins have some sequence similarity to several members ofthe glucagon-like peptide family, with the highest homology, 53%, beingto GLP-1[7-36]NH₂ (Goke, et al., J. Biol. Chem., 268:19650-55, 1993).GLP-1[7-36]NH₂, also known as proglucagon[78-107] and most commonly as“GLP-1,” has an insulinotropic effect, stimulating insulin secretionfrom pancreatic β-cells; GLP-1 also inhibits glucagon secretion frompancreatic α-cells (Orskov, et al., Diabetes, 42:658-61, 1993;D'Alessio, et al., J. Clin. Invest., 97:133-38, 1996). GLP-1 is reportedto inhibit gastric emptying (Williams B, et al., J Clin Encocrinol Metab81 (1): 327-32, 1996; Wettergren A, et al., Dig Dis Sci 38 (4): 665-73,1993), and gastric acid secretion. (Schjoldager B T, et al., Dig Dis Sci34 (5): 703-8, 1989; O'Halloran D J, et al., J Endocrinol 126 (1):169-73, 1990; Wettergren A, et al., Dig Dis Sci 38 (4): 665-73, 1993).GLP-1[7-37], which has an additional glycine residue at its carboxyterminus, also stimulates insulin secretion in humans (Orskov, et al.,Diabetes, 42:658-61, 1993). A transmembrane G-proteinadenylate-cyclase-coupled receptor believed to be responsible for theinsulinotropic effect of GLP-1 is reported to have been cloned from aβ-cell line (Thorens, Proc. Natl. Acad. Sci. USA 89:8641-45 (1992)).

Exendin-4 potently binds at GLP-1 receptors on insulin-secreting βTC1cells, at dispersed acinar cells from guinea pig pancreas, and atparietal cells from stomach; the peptide is also said to stimulatesomatostatin release and inhibit gastrin release in isolated stomachs(Goke, et al., J. Biol. Chem. 268:19650-55, 1993; Schepp, et al., Eur.J. Pharmacol., 69:183-91, 1994; Eissele, et al., Life Sci., 55:629-34,1994). Exendin-3 and exendin-4 were reported to stimulate cAMPproduction in, and amylase release from, pancreatic acinar cells(Malhotra, R., et al., Regulatory Peptides, 41:149-56, 1992; Raufman, etal., J. Biol. Chem. 267:21432-37, 1992; Singh, et al., Regul. Pept.53:47-59, 1994). The use of exendin-3 and exendin-4 as insulinotropicagents for the treatment of diabetes mellitus and the prevention ofhyperglycemia has been proposed (Eng, U.S. Pat. No. 5,424,286).

C-terminally truncated exendin peptides such as exendin-4[9-39], acarboxyamidated molecule, and fragments 3-39 through 9-39 have beenreported to be potent and selective antagonists of GLP-1 (Goke, et al.,J. Biol. Chem., 268:19650-55, 1993; Raufman, J. P., et al., J. Biol.Chem. 266:2897-902, 1991; Schepp, W., et al., Eur. J. Pharm. 269:183-91,1994; Montrose-Rafizadeh, et al., Diabetes, 45(Suppl. 2):152A, 1996).Exendin-4[9-39] is said to block endogenous GLP-1 in vivo, resulting inreduced insulin secretion. Wang, et al., J. Clin. Invest., 95:417-21,1995; D'Alessio, et al., J. Clin. Invest., 97:133-38, 1996). Thereceptor apparently responsible for the insulinotropic effect of GLP-1has reportedly been cloned from rat pancreatic islet cell (Thorens, B.,Proc. Natl. Acad. Sci. USA 89:8641-8645, 1992). Exendins andexendin-4[9-39] are said to bind to the cloned GLP-1 receptor (ratpancreatic β-cell GLP-1 receptor (Fehmann H C, et al., Peptides 15 (3):453-6, 1994) and human GLP-1 receptor (Thorens B, et al., Diabetes 42(11): 1678-82, 1993). In cells transfected with the cloned GLP-1receptor, exendin-4 is reportedly an agonist, i.e., it increases cAMP,while exendin[9-39] is identified as an antagonist, i.e., it blocks thestimulatory actions of exendin-4 and GLP-1. Id.

Exendin-4[9-39] is also reported to act as an antagonist of the fulllength exendins, inhibiting stimulation of pancreatic acinar cells byexendin-3 and exendin-4 (Raufman, et al., J. Biol. Chem. 266:2897-902,1991; Raufman, et al., J. Biol. Chem., 266:21432-37, 1992). It is alsoreported that exendin[9-39] inhibits the stimulation of plasma insulinlevels by exendin-4, and inhibits the somatostatin release-stimulatingand gastrin release-inhibiting activities of exendin-4 and GLP-1(Kolligs, F., et al., Diabetes, 44:16-19, 1995; Eissele, et al., LifeSciences, 55:629-34, 1994).

Methods for regulating gastrointestinal motility using exendin agonistsare described and claimed in U.S. application Ser. No. 08/908,867, filedAug. 8, 1997, entitled, “Methods for Regulating GastrointestinalMotility,” which application is a continuation-in-part of U.S.application Ser. No. 08/694,954, filed Aug. 8, 1996, which enjoys commonownership with the present invention and is hereby incorporated byreference.

Methods of reducing food intake using exendin agonists are described andclaimed in U.S. application Ser. No. 09/003,869, filed Jan. 7, 1998,entitled, “Use of Exendin and Agonists Thereof for the Reduction of FoodIntake,” claiming the benefit of Provisional Application No. 60/034,905,filed Jan. 7, 1997, No. 60/055,404, filed Aug. 7, 1997, No. 60/065,442filed Nov. 14, 1997, and No. 60/066,029 filed Nov. 14, 1997. Theseapplications also enjoy common ownership with the present invention andare hereby incorporated by reference.

Exendins have also been found to have inotropic and diuretic effects.International Application No. PCT/US99/02554, filed Feb. 5, 1999, 1998,claiming the benefit of Provisional Application No. 60/075,122, filedFeb. 13, 1998. These applications also enjoy common ownership with thepresent invention and are hereby incorporated by reference.

Additionally, exendins have been found to suppress glucagon secretion(U.S. Provisional Application No. 60/132,017, entitled, “Methods forGlucagon Suppression,” filed Apr. 30, 1999, which enjoys commonownership with the present invention and is hereby incorporated byreference).

Exendin [9-39] has been used to investigate the physiological relevanceof central GLP-1 in control of food intake (Turton, M. D. et al. Nature379:69-72, 1996). GLP-1 administered by intracerebroventricularinjection inhibits food intake in rats. This satiety-inducing effect ofGLP-1 delivered ICV is reported to be inhibited by ICV injection ofexendin [9-39] (Turton, supra). However, it has been reported that GLP-1does not inhibit food intake in mice when administered by peripheralinjection (Turton, M. D., Nature 379:69-72, 1996; Bhavsar, S. P., Soc.Neurosci. Abstr. 21:460 (188.8), 1995).

SUMMARY OF THE INVENTION

The present invention concerns the surprising discovery that exendinsand exendin agonists do not cross the placenta, and yet have a profoundand prolonged effect on blood glucose, rendering them ideal agents forthe treatment of gestational diabetes mellitus.

The present invention is directed to novel methods for treatinggestational diabetes mellitus comprising the administration of anexendin, for example, exendin-3 (SEQ ID NO. 1: His Ser Asp Gly Thr PheThr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile GluTrp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser), orexendin-4 (SEQ ID NO. 2: His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser LysGln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly GlyPro Ser Ser Gly Ala Pro Pro Pro Ser), or other compounds whicheffectively bind to the receptor at which exendin exerts its actionswhich are beneficial in the treatment of gestational diabetes mellitus.

In a first aspect, the invention features a method of treatinggestational diabetes mellitus in a subject comprising administering tothe subject a therapeutically effective amount of an exendin or anexendin agonist. By an “exendin agonist” is meant a compound that mimicsthe effects of exendin in the treatment of gestational diabetes mellitusby binding to the receptor or receptors where exendin causes one or moreof these effects. Exendins and exendin agonist should be especiallybeneficial in the treatment of GDM because, due to their actions toinhibit gastric emptying, administration of such compounds should notresult in increased weight gain. Additionally, in animal and humanstudies to date, administration of exendins and exendin agonists havenot resulted in an increased incidence of hypoglycemia.

Exendin agonist compounds include exendin acids, for example exendin-3acid and exendin-4 acid. Preferred exendin agonist compounds includethose described in International Application No. PCT/US98/16387,entitled, “Novel Exendin Agonist Compounds,” filed Aug. 6, 1998,claiming the benefit of U.S. Provisional Patent Application Ser. No.60/055,404, filed Aug. 8, 1997; International Application No.PCT/US98/24210 entitled, “Novel Exendin Agonist Compounds,” filed Nov.13, 1998, claiming priority on U.S. Provisional Patent Application Ser.No. 60/065,442, filed Nov. 14, 1997; and International Application No.PCT/US98/24273 entitled, “Novel Exendin Agonist Compounds,” filed Nov.13, 1998, claiming priority on U.S. Provisional Patent Application Ser.No. 60/066,029, filed Nov. 14, 1997; all of which enjoy common ownershipwith the present application and all of which are incorporated by thisreference into the present application as though fully set forth herein.Additional preferred exendin agonist compounds are those described andclaimed in U.S. Provisional Application Ser. No. 60/132,018, entitled,“Modified Exendins and Exendin Agonists,” filed Apr. 30, 1999, whichenjoys common ownership with the present application and which isincorporated by this reference into the present application as thoughfully set forth herein.

By “gestational diabetes mellitus” or “GDM” is meant any degree ofglucose intolerance with onset or first recognition during pregnancy.

Thus, in a first embodiment, the present invention provides a method fortreating gestational diabetes in a subject comprising administering tosaid subject a therapeutically effective amount of an exendin or anexendin agonist. Preferred exendin agonist compounds include thosedescribed in International Application Nos. PCT/US98/16387,PCT/US98/24210, and PCT/US98/24273, which have been incorporated byreference in the present application. Preferably, the subject is avertebrate, more preferably a mammal, and most preferably a human woman.In preferred aspects, the exendin or exendin agonist is administeredparenterally, more preferably by injection. In a most preferred aspect,the injection is a peripheral injection. Preferably, about 1 μg-30 μg toabout 1 mg of the exendin or exendin agonist is administered per day.More preferably, about 1-30 μg to about 500 μg, or about 1-30 μg toabout 50 μg of the exendin or exendin agonist is administered per day.Most preferably, about 3 μg to about 50 μg of the exendin or exendinagonist is administered per day.

In one preferred aspect, the exendin or exendin agonist used in themethods of the present invention is exendin-3. In another preferredaspect, said exendin is exendin-4. Other preferred exendin agonistsinclude exendin-4 (1-30) (SEQ ID NO 6: His Gly Glu Gly Thr Phe Thr SerAsp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp LeuLys Asn Gly Gly), exendin-4 (1-30) amide (SEQ ID NO 7: His Gly Glu GlyThr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu PheIle Glu Trp Leu Lys Asn Gly Gly-NH₂), exendin-4 (1-28) amide (SEQ ID NO40: His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu GluAla Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂), ¹⁴Leu, ²⁵Phe exendin-4amide (SEQ ID NO 9: His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnLeu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly ProSer Ser Gly Ala Pro Pro Pro Ser-NH₂), ¹⁴Leu, ²⁵Phe exendin-4 (1-28)amide (SEQ ID NO 41: His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnLeu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂), and¹⁴Leu, ²²Ala, ²⁵Phe exendin-4 (1-28) amide (SEQ ID NO 8: His Gly Glu GlyThr Phe Thr Ser Asp Leu Ser Lys Gln Leu Glu Glu Glu Ala Val Arg Leu AlaIle Glu Phe Leu Lys Asn-NH₂).

In the methods of the present invention, the exendins and exendinagonists may be administered separately or together with one or moreother compounds and compositions that exhibit a long-term or short-termblood glucose control action, including, but not limited to othercompounds and compositions that comprise an insulin or an amylinagonist. Suitable amylin agonists include, for example,(^(25,28,29)Pro)-human amylin (also known as “pramlintide,” previouslyreferred to as “AC-137,” and, referred to in its acetate salt form byits trademark SYMLIN® (pramlintide acetate), as described in “AmylinAgonist Peptides and Uses Therefor,” U.S. Pat. No. 5,686,411, issuedNov. 11, 1997, and salmon calcitonin.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the amino acid sequences for certain exendin agonistcompounds useful in the present invention (SEQ ID NOs 9-39).

FIG. 2 depicts concentrations of exendin-4 (AC2993) in plasma andamniotic fluid of rats after 21 μg subcutaneous injection.

FIG. 3 depicts concentrations of exendin-4 (AC2993) in plasma andamniotic fluid of rats after 210 μg subcutaneous injection.

DETAILED DESCRIPTION OF THE INVENTION

Exendins and exendin agonists are useful as described herein in view oftheir pharmacological properties. Activity as exendin agonists can beindicated by activity in the assays described below. Effects of exendinsor exendin agonists in treating gestational diabetes can be identified,evaluated, or screened for, using the methods described in the Examplesbelow, or other methods known in the art for determining effects onblood glucose control.

Exendin Agonist Compounds

Exendin agonist compounds are those described in InternationalApplication No. PCT/US98/16387, filed Aug. 6, 1998, entitled, “NovelExendin Agonist Compounds,” which claims the benefit of U.S. ProvisionalApplication No. 60/055,404, filed Aug. 8, 1997, including compounds ofthe formula (I) (SEQ ID NO. 3):

Xaa₁ Xaa₂ Xaa₃ Gly Thr Xaa₄ Xaa₅ Xaa₆ Xaa₇ Xaa₈ Ser Lys Gln Xaa₉ Glu GluGlu Ala Val Arg Leu Xaa₁₀ Xaa₁₁ Xaa₁₂ Xaa₁₃ Leu Lys Asn Gly Gly Xaa₁₄Ser Ser Gly Ala Xaa₁₅ Xaa₁₆ Xaa₁₇ Xaa₁₈-Z

wherein

Xaa₁ is His, Arg or Tyr;

Xaa₂ is Ser, Gly, Ala or Thr;

Xaa₃ is Asp or Glu;

Xaa₄ is Phe, Tyr or naphthylalanine;

Xaa₅ is Thr or Ser;

Xaa₆ is Ser or Thr;

Xaa₇ is Asp or Glu;

Xaa₈ is Leu, Ile, Val, pentylglycine or Met;

Xaa₉ is Leu, Ile, pentylglycine, Val or Met;

Xaa₁₀, is Phe, Tyr or naphthylalanine;

Xaa₁₁ is Ile, Val, Leu, pentylglycine, tert-butylglycine or Met;

Xaa₁₂ is Glu or Asp;

Xaa₁₃ is Trp, Phe, Tyr, or naphthylalanine;

Xaa₁₄, Xaa₁₅, Xaa₁₆ and Xaa₁₇ are independently Pro, homoproline, 3Hyp,4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine orN-alkylalanine;

Xaa₁₈ is Ser, Thr or Tyr; and

Z is —OH or —NH₂;

with the proviso that the compound is not exendin-3 or exendin-4.

Preferred N-alkyl groups for N-alkylglycine, N-alkylpentylglycine andN-alkylalanine include lower alkyl groups preferably of 1 to about 6carbon atoms, more preferably of 1 to 4 carbon atoms. Suitable compoundsinclude those listed in FIG. 10 having amino acid sequences of SEQ IDNOs 9 to 39.

Preferred exendin agonist compounds include those wherein Xaa₁ is H isor Tyr. More preferably Xaa₁ is His.

Preferred are those compounds wherein Xaa₂ is Gly.

Preferred are those compounds wherein Xaa₉ is Leu, pentylglycine or Met.

Preferred compounds include those wherein Xaa₁₃ is Trp or Phe.

Also preferred are compounds where Xaa₄ is Phe or naphthylalanine; Xaa₁₁is Ile or Val and Xaa₁₄, Xaa₁₅, Xaa₁₆ and Xaa₁₇ are independentlyselected from Pro, homoproline, thioproline or N-alkylalanine.Preferably N-alkylalanine has a N-alkyl group of 1 to about 6 carbonatoms.

According to an especially preferred aspect, Xaa₁₅, Xaa₁₆ and Xaa₁₇ arethe same amino acid reside.

Preferred are compounds wherein Xaa₁₈ is Ser or Tyr, more preferablySer.

Preferably Z is —NH₂.

According to one aspect, preferred are compounds of formula (I) whereinXaa₁ is H is or Tyr, more preferably H is; Xaa₂ is Gly; Xaa₄ is Phe ornaphthylalanine; Xaa₉ is Leu, pentylglycine or Met; Xaa₁₀ is Phe ornaphthylalanine; Xaa₁₁ is Ile or Val; Xaa₁₄, Xaa₁₅, Xaa₁₆ and Xaa₁₇ areindependently selected from Pro, homoproline, thioproline orN-alkylalanine; and Xaa₁₈ is Ser or Tyr, more preferably Ser. Morepreferably Z is —NH₂.

According to an especially preferred aspect, especially preferredcompounds include those of formula (I) wherein: Xaa₁ is H is or Arg;Xaa₂ is Gly; Xaa₃ is Asp or Glu; Xaa₄ is Phe or napthylalanine; Xaa₅ isThr or Ser; Xaa₆ is Ser or Thr; Xaa₇ is Asp or Glu; Xaa₈ is Leu orpentylglycine; Xaa₉ is Leu or pentylglycine; Xaa₁₀ is Phe ornaphthylalanine; Xaa₁₁ is Ile, Val or t-butyltylglycine; Xaa₁₂ is Glu orAsp; Xaa₁₃ is Trp or Phe; Xaa₁₄, Xaa₁₅, Xaa₁₆, and Xaa₁₇ areindependently Pro, homoproline, thioproline, or N-methylalanine; Xaa₁₈is Ser or Tyr: and Z is —OH or —NH₂; with the proviso that the compounddoes not have the formula of either SEQ ID NOs 1 or 2. More preferably Zis —NH₂. Especially preferred compounds include those having the aminoacid sequence of SEQ ID NOs 9, 10, 21, 22, 23, 26, 28, 34, 35 and 39.

According to an especially preferred aspect, provided are compoundswhere Xaa₉ is Leu, Ile, Val or pentylglycine, more preferably Leu orpentylglycine, and Xaa₁₃ is Phe, Tyr or naphthylalanine, more preferablyPhe or naphthylalanine. These compounds will exhibit advantageousduration of action and be less subject to oxidative degradation, both invitro and in vivo, as well as during synthesis of the compound.

Exendin agonist compounds also include those described in InternationalApplication No. PCT/US98/24210, filed Nov. 13, 1998, entitled, “NovelExendin Agonist compounds,” which claims the benefit of U.S. ProvisionalApplication No. 60/065,442, filed Nov. 14, 1997, including compounds ofthe formula (II) (SEQ ID NO. 4):

Xaa₁  Xaa₂  Xaa₃ Gly Xaa₅  Xaa₆  Xaa₇  Xaa₈  Xaa₉ Xaa₁₀  Xaa₁₁  Xaa₁₂ Xaa₁₃  Xaa₁₄  Xaa₁₅  Xaa₁₆  Xaa₁₇ Ala Xaa₁₉  Xaa₂₀  Xaa₂₁  Xaa₂₂  Xaa₂₃ Xaa₂₄  Xaa₂₅ Xaa₂₆  Xaa₂₇  Xaa₂₈-Z₁;

wherein

Xaa₁ is His, Arg or Tyr;

Xaa₂ is Ser, Gly, Ala or Thr;

Xaa₃ is Asp or Glu;

Xaa₅ is Ala or Thr;

Xaa₆ is Ala, Phe, Tyr or naphthylalanine;

Xaa₇ is Thr or Ser;

Xaa₈ is Ala, Ser or Thr;

Xaa₉ is Asp or Glu;

Xaa₁₀ is Ala, Leu, Ile, Val, pentylglycine or Met;

Xaa₁₁ is Ala or Ser;

Xaa₁₂ is Ala or Lys;

Xaa₁₃ is Ala or Gln;

Xaa₁₄ is Ala, Leu, Ile, pentylglycine, Val or Met;

Xaa₁₅ is Ala or Glu;

Xaa₁₆ is Ala or Glu;

Xaa₁₇ is Ala or Glu;

Xaa₁₉ is Ala or Val;

Xaa₂₀ is Ala or Arg;

Xaa₂₁ is Ala or Leu;

Xaa₂₂ is Ala, Phe, Tyr or naphthylalanine;

Xaa₂₃ is Ile, Val, Leu, pentylglycine, tert-butylglycine or Met;

Xaa₂₄ is Ala, Glu or Asp;

Xaa₂₅ is Ala, Trp, Phe, Tyr or naphthylalanine;

Xaa₂₆ is Ala or Leu;

Xaa₂₇ is Ala or Lys;

Xaa₂₈ is Ala or Asn;

(SEQ ID NO. 4) Z₁ is OH, NH₂, Gly-Z₂, Gly Gly-Z₂, Gly Gly Xaa₃₁-Z₂, GlyGly Xaa₃₁ Ser-Z₂, Gly Gly Xaa₃₁ Ser Ser-Z₂, Gly Gly Xaa₃₁ Ser SerGly-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly Ala-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly AlaXaa₃₆-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆ Xaa₃₇-Z₂, or Gly GlyXaa₃₁ Ser Ser Gly Ala Xaa₃₆ Xaa₃₇ Xaa₃₈-Z₂;

Xaa₃₁, Xaa₃₆, Xaa₃₇ and Xaa₃₈ are independently Pro, homoproline, 3Hyp,4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine orN-alkylalanine; and

Z₂ is —OH or —NH₂;

provided that no more than three of Xaa₃, Xaa₅, Xaa₆, Xaa₈, Xaa₁₀,Xaa₁₁, Xaa₁₂, Xaa₁₃, Xaa₁₄, Xaa₁₅, Xaa₁₆, Xaa₁₇, Xaa₁₉, Xaa₂₀, Xaa₂₁,Xaa₂₄, Xaa₂₅, Xaa₂₆, Xaa₂₇ and Xaa₂₈ are Ala.

Preferred N-alkyl groups for N-alkylglycine, N-alkylpentylglycine andN-alkylalanine include lower alkyl groups preferably of 1 to about 6carbon atoms, more preferably of 1 to 4 carbon atoms.

Preferred exendin agonist compounds include those wherein Xaa₁ is H isor Tyr. More preferably Xaa₁ is His.

Preferred are those compounds wherein Xaa₂ is Gly.

Preferred are those compounds wherein Xaa₁₄ is Leu, pentylglycine orMet.

Preferred compounds are those wherein Xaa₂₅ is Trp or Phe.

Preferred compounds are those where Xaa₆ is Phe or naphthylalanine;Xaa₂₂ is Phe or naphthylalanine and Xaa₂₃ is Ile or Val.

Preferred are compounds wherein Xaa₃₁, Xaa₃₆, Xaa₃₇ and Xaa₃₈ areindependently selected from Pro, homoproline, thioproline andN-alkylalanine.

Preferably Z₁ is —NH₂.

Preferable Z₂ is —NH₂.

According to one aspect, preferred are compounds of formula (II) whereinXaa₁ is H is or Tyr, more preferably His; Xaa₂ is Gly; Xaa₆ is Phe ornaphthylalanine; Xaa₁₄ is Leu, pentylglycine or Met; Xaa₂₂ is Phe ornaphthylalanine; Xaa₂₃ is Ile or Val; Xaa₃₁, Xaa₃₆, Xaa₃₇ and Xaa₃₈ areindependently selected from Pro, homoproline, thioproline orN-alkylalanine. More preferably Z₁ is —NH₂.

According to an especially preferred aspect, especially preferredcompounds include those of formula (II) wherein: Xaa₁ is His or Arg;Xaa₂ is Gly or Ala; Xaa₃ is Asp or Glu; Xaa₅ is Ala or Thr; Xaa₆ is Ala,Phe or naphthylalanine; Xaa₇ is Thr or Ser; Xaa₈ is Ala, Ser or Thr;Xaa₉ is Asp or Glu; Xaa₁₀ is Ala, Leu or pentylglycine; Xaa₁₁ is Ala orSer; Xaa₁₂ is Ala or Lys; Xaa₁₃ is Ala or Gln; Xaa₁₄ is Ala, Leu orpentylglycine; Xaa₁₅ is Ala or Glu; Xaa₁₆ is Ala or Glu; Xaa₁₇ is Ala orGlu; Xaa₁₉ is Ala or Val; Xaa₂₀ is Ala or Arg; Xaa₂₁, is Ala or Leu;Xaa₂₂ is Phe or naphthylalanine; Xaa₂₃ is Ile, Val or tert-butylglycine;Xaa₂₄ is Ala, Glu or Asp; Xaa₂₅ is Ala, Trp or Phe; Xaa₂₆ is Ala or Leu;Xaa₂₇ is Ala or Lys; Xaa₂₈ is Ala or Asn; Z₁ is —OH, —NH₂, Gly-Z₂, GlyGly-Z₂, Gly Gly Xaa₃₁-Z₂, Gly Gly Xaa₃₁ Ser-Z₂, Gly Gly Xaa₃₁ SerSer-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly Ala-Z₂,Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly AlaXaa₃₆ Xaa₃₇-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆ Xaa₃₇ Xaa₃₈-Z₂;Xaa₃₁, Xaa₃₆, Xaa₃₇ and Xaa₃₈ being independently Pro homoproline,thioproline or N-methylalanine; and Z₂ being —OH or —NH₂; provided thatno more than three of Xaa₃, Xaa₅, Xaa₆, Xaa₈, Xaa₁₀, Xaa₁₁, Xaa₁₂,Xaa₁₃, Xaa₁₄, Xaa₁₅, Xaa₁₆, Xaa₁₇, Xaa₁₈, Xaa₂₀, Xaa₂₁, Xaa₂₄, Xaa₂₅,Xaa₂₆, Xaa₂₇ and Xaa₂₈ are Ala. Especially preferred compounds includethose having the amino acid sequence of SEQ ID NOs 40-61.

According to an especially preferred aspect, provided are compoundswhere Xaa₁₄ is Leu, Ile, Val or pentylglycine, more preferably Leu orpentylglycine, and Xaa₂₅ is Phe, Tyr or naphthylalanine, more preferablyPhe or naphthylalanine. These compounds will be less susceptive tooxidative degradation, both in vitro and in vivo, as well as during

Synthesis of the Compound

Exendin agonist compounds also include those described in InternationalPatent Application No. PCT/US98/24273, filed Nov. 13, 1998, entitled,“Novel Exendin Agonist Compounds,” which claims the benefit of U.S.Provisional Application No. 60/066,029, filed Nov. 14, 1997, includingcompounds of the formula (III) (SEQ ID NO. 5):

Xaa₁ Xaa₂ Xaa₃ Xaa₄ Xaa₅ Xaa₆ Xaa₇ Xaa₈ Xaa₉ Xaa₁₀Xaa₁₁ Xaa₁₂ Xaa₁₃ Xaa₁₄ Xaa₁₅ Xaa₁₆ Xaa₁₇ AlaXaa₁₉ Xaa₂₀ Xaa₂₁ Xaa₂₂ Xaa₂₃ Xaa₂₄ Xaa₂₅ Xaa₂₆, Xaa₂₇ Xaa₂₈-Z₁;

-   -   wherein

Xaa₁ is His, Arg, Tyr, Ala, Norval, Val or Norleu;

Xaa₂ is Ser, Gly, Ala or Thr;

Xaa₃ is Ala, Asp or Glu;

Xaa₄ is Ala, Norval, Val, Norleu or Gly;

Xaa₅ is Ala or Thr;

Xaa₆ is Phe, Tyr or naphthylalanine;

Xaa₇ is Thr or Ser;

Xaa₈ is Ala, Ser or Thr;

Xaa₉ is Ala, Norval, Val, Norleu, Asp or Glu;

Xaa₁₀ is Ala, Leu, Ile, Val, pentylglycine or Met;

Xaa₁₁ is Ala or Ser;

Xaa₁₂ is Ala or Lys;

Xaa₁₃ is Ala or Gln;

Xaa₁₄ is Ala, Leu, Ile, pentylglycine, Val or Met;

Xaa₁₅ is Ala or Glu;

Xaa₁₆ is Ala or Glu;

Xaa₁₇ is Ala or Glu;

Xaa₁₉ is Ala or Val;

Xaa₂₀ is Ala or Arg;

Xaa₂₁ is Ala or Leu;

Xaa₂₂ is Phe, Tyr or naphthylalanine;

Xaa₂₃ is Ile, Val, Leu, pentylglycine, tert-butylglycine or Met;

Xaa₂₄ is Ala, Glu or Asp;

Xaa₂₅ is Ala, Trp, Phe, Tyr or naphthylalanine;

Xaa₂₆ is Ala or Leu;

Xaa₂₇ is Ala or Lys;

Xaa₂₈ is Ala or Asn;

(SEQ ID NO. 5) Z₁ is OH, NH₂, Gly-Z₂, Gly Gly-Z₂, Gly Gly Xaa₃₁-Z₂, GlyGly Xaa₃₁ Ser-Z₂, Gly Gly Xaa₃₁ Ser Ser-Z₂, Gly Gly Xaa₃₁ Ser SerGly-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly Ala-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly AlaXaa₃₆-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆ Xaa₃₇-Z₂, Gly GlyXaa₃₁ Ser Ser Gly Ala Xaa₃₆ Xaa₃₇ Xaa₃₈-Z₂, or Gly Gly Xaa₃₁ Ser Ser GlyAla Xaa₃₆ Xaa₃₇ Xaa₃₈ Xaa₃₉-Z₂;

wherein Xaa₃₁, Xaa₃₆, Xaa₃₇ and Xaa₃₈ are independently Pro,homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine,N-alkylpentylglycine or N-alkylalanine; and

Z₂ is —OH or —NH₂;

provided that no more than three of Xaa₃, Xaa₄, Xaa₅, Xaa₆, Xaa₈, Xaa₉,Xaa₁₀, Xaa₁₁, Xaa₁₂, Xaa₁₃, Xaa₁₄, Xaa₁₅, Xaa₁₆, Xaa₁₇, Xaa₁₉, Xaa₂₀,Xaa₂₁, Xaa₂₄, Xaa₂₅, Xaa₂₆, Xaa₂₇ and Xaa₂₈ are Ala; and provided alsothat, if Xaa₁ is His, Arg or Tyr, then at least one of Xaa₃, Xaa₄ andXaa₉ is Ala.

DEFINITIONS

In accordance with the present invention and as used herein, thefollowing terms are defined to have the following meanings, unlessexplicitly stated otherwise.

The term “amino acid” refers to natural amino acids, unnatural aminoacids, and amino acid analogs, all in their D and L stereoisomers iftheir structure allow such stereoisomeric forms. Natural amino acidsinclude alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid(Asp), cysteine (Cys), glutamine (Gln), glutamic acid (Glu), glycine(Gly), histidine (His), isoleucine (Ile), leucine (Leu), Lysine (Lys),methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser),threonine (Thr), tryptophan (Trp), tyrosine (Tyr) and valine (Val).Unnatural amino acids include, but are not limited toazetidinecarboxylic acid, 2-aminoadipic acid, 3-aminoadipic acid,beta-alanine, aminopropionic acid, 2-aminobutyric acid, 4-aminobutyricacid, 6-aminocaproic acid, 2-aminoheptanoic acid, 2-aminoisobutyricacid, 3-aminoisbutyric acid, 2-aminopimelic acid, tertiary-butylglycine,2,4-diaminoisobutyric acid, desmosine, 2,2′-diaminopimelic acid,2,3-diaminopropionic acid, N-ethylglycine, N-ethylasparagine,homoproline, hydroxylysine, allo-hydroxylysine, 3-hydroxyproline,4-hydroxyproline, isodesmosine, allo-isoleucine, N-methylalanine,N-methylglycine, N-methylisoleucine, N-methylpentylglycine,N-methylvaline, naphthalanine, norvaline, norleucine, ornithine,pentylglycine, pipecolic acid and thioproline. Amino acid analogsinclude the natural and unnatural amino acids which are chemicallyblocked, reversibly or irreversibly, or modified on their N-terminalamino group or their side-chain groups, as for example, methioninesulfoxide, methionine sulfone, S-(carboxymethyl)-cysteine,S-(carboxymethyl)-cysteine sulfoxide and S-(carboxymethyl)-cysteinesulfone.

The term “amino acid analog” refers to an amino acid wherein either theC-terminal carboxy group, the N-terminal amino group or side-chainfunctional group has been chemically codified to another functionalgroup. For example, aspartic acid-(beta-methyl ester) is an amino acidanalog of aspartic acid; N-ethylglycine is an amino acid analog ofglycine; or alanine carboxamide is an amino acid analog of alanine.

The term “amino acid residue” refers to radicals having the structure:(1) —C(O)—R—NH—, wherein R typically is —CH(R′)—, wherein R′ is an aminoacid side chain, typically H or a carbon containing substituent; or (2)

wherein p is 1, 2 or 3 representing the azetidinecarboxylic acid,proline or pipecolic acid residues, respectively.

The term “lower” referred to herein in connection with organic radicalssuch as alkyl groups defines such groups with up to and including about6, preferably up to and including 4 and advantageously one or two carbonatoms. Such groups may be straight chain or branched chain.

“Pharmaceutically acceptable salt” includes salts of the compoundsdescribed herein derived from the combination of such compounds and anorganic or inorganic acid. In practice the use of the salt form amountsto use of the base form. The compounds are useful in both free base andsalt form.

In addition, the following abbreviations stand for the following: “ACN”or “CH₃ CN” refers to acetonitrile. “Boa”, “tBoc” or “Tboc” refers tot-butoxy carbonyl. “DCC” refers to N,N′-dicyclohexylcarbodiimide. “Fmoc”refers to fluorenylmethoxycarbonyl. “HBTU” refers to2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate.“HOBt” refers to 1-hydroxybenzotriazole monohydrate. “homoP” or hPro”refers to homoproline. “MeAla” or “Nme” refers to N-methylalanine.“naph” refers to naphthylalanine. “pG” or pGly” refers to pentylglycine.“tBuG” refers to tertiary-butylglycine. “ThioP” or tPro” refers tothioproline. 3Hyp” refers to 3-hydroxyproline 4Hyp” refers to4-hydroxyproline NAG” refers to N-alkylglycine NAPG” refers toN-alkylpentylglycine “Norval” refers to norvaline “Norleu” refers tonorleucine

Preparation of Compounds

The exendins and exendin agonists described herein may be prepared usingstandard solid-phase peptide synthesis techniques and preferably anautomated or semiautomated peptide synthesizer. Typically, using suchtechniques, an α-N-carbamoyl protected amino acid and an amino acidattached to the growing peptide chain on a resin are coupled at roomtemperature in an inert solvent such as dimethylformamide,N-methylpyrrolidinone or methylene chloride in the presence of couplingagents such as dicyclohexylcarbodiimide and 1-hydroxybenzotriazole inthe presence of a base such as diisopropylethylamine. The α-N-carbamoylprotecting group is removed from the resulting peptide-resin using areagent such as trifluoroacetic acid or piperidine, and the couplingreaction repeated with the next desired N-protected amino acid to beadded to the peptide chain. Suitable N-protecting groups are well knownin the art, with t-butyloxycarbonyl (tBoc) and fluorenylmethoxycarbonyl(Fmoc) being preferred herein.

The solvents, amino acid derivatives and 4-methylbenzhydryl-amine resinused in the peptide synthesizer may be purchased from Applied BiosystemsInc. (Foster City, Calif.). The following side-chain protected aminoacids may be purchased from Applied Biosystems, Inc.: Boc-Arg(Mts),Fmoc-Arg(Pmc), Boc-Thr(Bzl), Fmoc-Thr(t-Bu), Boc-Ser(Bzl),Fmoc-Ser(t-Bu), Boc-Tyr(BrZ), Fmoc-Tyr(t-Bu), Boc-Lys(Cl-Z),Fmoc-Lys(Boc), Boc-Glu(Bzl), Fmoc-Glu(t-Bu), Fmoc-His(Trt),Fmoc-Asn(Trt), and Fmoc-Gln(Trt). Boc-His(BOM) may be purchased fromApplied Biosystems, Inc. or Bachem Inc. (Torrance, Calif.). Anisole,dimethylsulfide, phenol, ethanedithiol, and thioanisole may be obtainedfrom Aldrich Chemical Company (Milwaukee, Wis.). Air Products andChemicals (Allentown, Pa.) supplies HF. Ethyl ether, acetic acid andmethanol may be purchased from Fisher Scientific (Pittsburgh, Pa.).

Solid phase peptide synthesis may be carried out with an automaticpeptide synthesizer (Model 430A, Applied Biosystems Inc., Foster City,Calif.) using the NMP/HOBt (Option 1) system and tBoc or Fmoc chemistry(see, Applied Biosystems User's Manual for the ABI 430A PeptideSynthesizer, Version 1.3B Jul. 1, 1988, section 6, pp. 49-70, AppliedBiosystems, Inc., Foster City, Calif.) with capping. Boc-peptide-resinsmay be cleaved with HF (−5° C. to 0° C., 1 hour). The peptide may beextracted from the resin with alternating water and acetic acid, and thefiltrates lyophilized. The Fmoc-peptide resins may be cleaved accordingto standard methods (Introduction to Cleavage Techniques, AppliedBiosystems, Inc., 1990, pp. 6-12). Peptides may be also be assembledusing an Advanced Chem Tech Synthesizer (Model MPS 350, Louisville,Ky.).

Peptides may be purified by RP-HPLC (preparative and analytical) using aWaters Delta Prep 3000 system. A C4, C8 or C18 preparative column (10μ,2.2×25 cm; Vydac, Hesperia, Calif.) may be used to isolate peptides, andpurity may be determined using a C4, C8 or C18 analytical column (5μ,0.46×25 cm; Vydac). Solvents (A=0.1% TFA/water and B=0.1% TFA/CH₃ CN)may be delivered to the analytical column at a flowrate of 1.0 ml/minand to the preparative column at 15 ml/min. Amino acid analyses may beperformed on the Waters Pico Tag system and processed using the Maximaprogram. Peptides may be hydrolyzed by vapor-phase acid hydrolysis (115°C., 20-24 h). Hydrolysates may be derivatized and analyzed by standardmethods (Cohen, et al., The Pico Tag Method: A Manual of AdvancedTechniques for Amino Acid Analysis, pp. 11-52, Millipore Corporation,Milford, Mass. (1989)). Fast atom bombardment analysis may be carriedout by M-Scan, Incorporated (West Chester, Pa.). Mass calibration may beperformed using cesium iodide or cesium iodide/glycerol. Plasmadesorption ionization analysis using time of flight detection may becarried out on an Applied Biosystems Bio-Ion 20 mass spectrometer.Electrospray mass spectroscopy may be carried out on a VG-Trio machine.

Peptide compounds useful in the invention may also be prepared usingrecombinant DNA techniques, using methods now known in the art. See,e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual, 2d Ed.,Cold Spring Harbor (1989). Non-peptide compounds useful in the presentinvention may be prepared by art-known methods. For example,phosphate-containing amino acids and peptides containing such aminoacids, may be prepared using methods known in the art. See, e.g.,Bartlett and Landen, Biorg. Chem. 14:356-377 (1986).

Compositions useful in the invention may conveniently be provided in theform of formulations suitable for parenteral (including intravenous,intramuscular and subcutaneous) or nasal or oral administration. In somecases, it will be convenient to provide an exendin or exendin agonistand another blood glucose-controlling, plasma glucose-lowering agent,such as an insulin, an amylin, an amylin agonist, in a singlecomposition or solution for administration together. In other cases, itmay be more advantageous to administer the additional agent separatelyfrom said exendin or exendin agonist. A suitable administration formatmay best be determined by a medical practitioner for each patientindividually. Suitable pharmaceutically acceptable carriers and theirformulation are described in standard formulation treatises, e.g.,Remington's Pharmaceutical Sciences by E. W. Martin. See also Wang, Y.J. and Hanson, M. A. “Parenteral Formulations of Proteins and Peptides:Stability and Stabilizers,” Journal of Parenteral Science andTechnology, Technical Report No. 10, Supp. 42:2S (1988).

Compounds useful in the invention can be provided as parenteralcompositions for injection or infusion. Preferred formulations are thosedescribed and claimed in U.S. Application Ser. No. 60/116,380, entitled,“Novel Exendin Agonist Formulations and Methods of AdministrationThereof,” filed Jan. 14, 1999, which enjoys common ownership with thepresent application and which is incorporated by this reference into thepresent application as though fully set forth herein. They can, forexample, be suspended in an inert oil, suitably a vegetable oil such assesame, peanut, olive oil, or other acceptable carrier. Preferably, theyare suspended in an aqueous carrier, for example, in an isotonic buffersolution at a pH of about 3.0 to 8.0, preferably at a pH of about 3.5 to5.0. These compositions may be sterilized by conventional sterilizationtechniques, or may be sterile filtered. The compositions may containpharmaceutically acceptable auxiliary substances as required toapproximate physiological conditions, such as pH buffering agents.Useful buffers include for example, sodium acetate/acetic acid buffers.A form of repository or “depot” slow release preparation may be used sothat therapeutically effective amounts of the preparation are deliveredinto the bloodstream over many hours or days following transdermalinjection or delivery.

The desired isotonicity may be accomplished using sodium chloride orother pharmaceutically acceptable agents such as dextrose, boric acid,sodium tartrate, propylene glycol, polyols (such as mannitol andsorbitol), or other inorganic or organic solutes. Sodium chloride ispreferred particularly for buffers containing sodium ions.

The claimed compositions can also be formulated as pharmaceuticallyacceptable salts (e.g., acid addition salts) and/or complexes thereof.Pharmaceutically acceptable salts are non-toxic salts at theconcentration at which they are administered. The preparation of suchsalts can facilitate the pharmacological use by altering thephysical-chemical characteristics of the composition without preventingthe composition from exerting its physiological effect. Examples ofuseful alterations in physical properties include lowering the meltingpoint to facilitate transmucosal administration and increasing thesolubility to facilitate the administration of higher concentrations ofthe drug.

Pharmaceutically acceptable salts include acid addition salts such asthose containing sulfate, hydrochloride, phosphate, sulfamate, acetate,citrate, lactate, tartrate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate.Pharmaceutically acceptable salts can be obtained from acids such ashydrochloric acid, sulfuric acid, phosphoric acid, sulfamic acid, aceticacid, citric acid, lactic acid, tartaric acid, malonic acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, cyclohexylsulfamic acid, and quinic acid. Suchsalts may be prepared by, for example, reacting the free acid or baseforms of the product with one or more equivalents of the appropriatebase or acid in a solvent or medium in which the salt is insoluble, orin a solvent such as water which is then removed in vacuo or byfreeze-drying or by exchanging the ions of an existing salt for anotherion on a suitable ion exchange resin.

Carriers or excipients can also be used to facilitate administration ofthe compound. Examples of carriers and excipients include calciumcarbonate, calcium phosphate, various sugars such as lactose, glucose,or sucrose, or types of starch, cellulose derivatives, gelatin,vegetable oils, polyethylene glycols and physiologically compatiblesolvents. The compositions or pharmaceutical composition can beadministered by different routes including intravenously,intraperitoneal, subcutaneous, and intramuscular, orally, topically,transmucosally, or by pulmonary inhalation.

If desired, solutions of the above compositions may be thickened with athickening agent such as methyl cellulose. They may be prepared inemulsified form, either water in oil or oil in water. Any of a widevariety of pharmaceutically acceptable emulsifying agents may beemployed including, for example, acacia powder, a non-ionic surfactant(such as a Tween), or an ionic surfactant (such as alkali polyetheralcohol sulfates or sulfonates, e.g., a Triton).

Compositions useful in the invention are prepared by mixing theingredients following generally accepted procedures. For example, theselected components may be simply mixed in a blender or other standarddevice to produce a concentrated mixture which may then be adjusted tothe final concentration and viscosity by the addition of water orthickening agent and possibly a buffer to control pH or an additionalsolute to control tonicity.

For use by the physician, the compositions will be provided in dosageunit form containing an amount of an exendin or exendin agonist, forexample, exendin-3, and/or exendin-4, with or without anotherglucose-lowering agent. Therapeutically effective amounts of an exendinor exendin agonist for use treating a subject with gestational diabetesmellitus are those that lower blood glucose to a desired level. As willbe recognized by those in the field, an effective amount of therapeuticagent will vary with many factors including the age and weight of thepatient, the patient's physical condition, the blood glucose level andother factors.

The effective daily blood glucose controlling dose of the compounds willtypically be in the range of about 3 to 30 μg to about 1 mg/day,preferably about 1 to 30 μg to about 500 μg/day and more preferablyabout 1 to 30 μg to about 100 μg/day, most preferably about 3 μg toabout 50 μg/day, for a 70 kg patient, administered in a single ordivided doses. Preferred dosages are described in U.S. Application Ser.No. 60/116,380, entitled, “Novel Exendin Agonist Formulations andMethods of Administration Thereof,” filed Jan. 14, 1999, which has beenincorporated by reference into the present application. A preferred dosefor twice daily administration is about 0.05 to about 0.3 μg perkilogram. The exact dose to be administered is determined by theattending clinician and is dependent upon where the particular compoundlies within the above quoted range, as well as upon the age, weight andcondition of the individual, and the mode of administration.Administration should begin shortly after diagnosis of GDM and continuefor the remainder of the gestation (i.e., the third trimester throughparturition).

Administration may be by injection, preferably subcutaneous orintramuscular. Administration may also be by non-injectable routes, forexample, via the respiratory tract, the mouth and the gut. Orally activecompounds may be taken orally, however dosages should be increased 5-10fold. Preferred methods of administration are described in U.S.Application Ser. No. 60/116,380, entitled, “Novel Exendin AgonistFormulations and Methods of Administration Thereof,” filed Jan. 14,1999, which has been incorporated by reference into the presentapplication. Solid dosage forms, such as those useful for oral, buccal,sublingual, intra-tracheal, nasal or pulmonary delivery may be used.Additionally, preserved or unpreserved liquid formulations or dry powdermay be used

The optimal formulation and mode of administration of compounds of thepresent application to a patient depend on factors known in the art suchas the particular disease or disorder, the desired effect, and the typeof patient. While the compounds will typically be used to treat humansubjects they may also be used to treat similar or identical diseases inother vertebrates such as other primates, farm animals such as swine,cattle and poultry, and sports animals and pets such as horses, dogs andcats.

To assist in understanding the present invention, the following Examplesare included. The experiments relating to this invention should not, ofcourse, be construed as specifically limiting the invention and suchvariations of the invention, now known or later developed, which wouldbe within the purview of one skilled in the art are considered to fallwithin the scope of the invention as described herein and hereinafterclaimed.

EXAMPLE 1 Preparation of Amidated Peptide Having SEQ ID NO. 9

The above-identified peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.). In general, single-coupling cycles were usedthroughout the synthesis and Fast Moc (HBTU activation) chemistry wasemployed. However, at some positions coupling was less efficient thanexpected and double couplings were required. In particular, residuesAsp₉, Thr₇ and Phe₆ all required double coupling. Deprotection (Fmocgroup removal) of the growing peptide chain using piperidine was notalways efficient. Double deprotection was required at positions Arg₂₀,Val₁₉ and Leu₁₄. Final deprotection of the completed peptide resin wasachieved using a mixture of triethylsilane (0.2 mL), ethanedithiol (0.2mL), anisole (0.2 mL), water (0.2 mL) and trifluoroacetic acid (15 mL)according to standard methods (Introduction to Cleavage Techniques,Applied Biosystems, Inc.) The peptide was precipitated in ether/water(50 mL) and centrifuged. The precipitate was reconstituted in glacialacetic acid and lyophilized. The lyophilized peptide was dissolved inwater). Crude purity was about 55%.

Used in purification steps and analysis were Solvent A (0.1% TFA inwater) and Solvent B (0.1% TFA in ACN).

The solution containing peptide was applied to a preparative C-18 columnand purified (10% to 40% Solvent B in Solvent A over 40 minutes). Purityof fractions was determined isocratically using a C-18 analyticalcolumn. Pure fractions were pooled furnishing the above-identifiedpeptide. Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent Aover 30 minutes) of the lyophilized peptide gave product peptide havingan observed retention time of 14.5 minutes. Electrospray MassSpectrometry (M): calculated 4131.7. found 4129.3.

EXAMPLE 2 Preparation of Peptide Having SEQ ID NO. 10

The above-identified peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 5. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 25% to 75% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 21.5 minutes. Electrospray Mass Spectrometry (M): calculated4168.6. found 4171.2.

EXAMPLE 3 Preparation of Peptide Having SEQ ID NO. 11

The above-identified peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 17.9 minutes. Electrospray Mass Spectrometry (M): calculated4147.6. found 4150.2.

EXAMPLE 3 Preparation of Peptide Having SEQ ID NO. 12

The above-identified peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 35% to 65% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 19.7 minutes. Electrospray Mass Spectrometry (M): calculated4212.6. found 4213.2.

EXAMPLE 4 Preparation of Peptide Having SEQ ID NO. 13

The above-identified peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 50% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 16.3 minutes. Electrospray Mass Spectrometry (M): calculated4262.7. found 4262.4.

EXAMPLE 5 Preparation of Peptide Having SEQ ID NO. 14

The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4172.6.

EXAMPLE 6 Preparation of Peptide Having SEQ ID NO. 15

The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4224.7.

EXAMPLE 7 Preparation of Peptide Having SEQ ID NO. 16

The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4172.6.

EXAMPLE 8 Preparation of Peptide Having SEQ ID NO. 17

The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4186.6.

EXAMPLE 9 Preparation of Peptide Having SEQ ID NO. 18

The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4200.7.

EXAMPLE 10 Preparation of Peptide Having SEQ ID NO. 19

The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4200.7.

EXAMPLE 11 Preparation of Peptide Having SEQ ID NO. 20

The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4202.7.

EXAMPLE 12 Preparation of Peptide Having SEQ ID NO. 21

The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4145.6.

EXAMPLE 13 Preparation of Peptide Having SEQ ID NO. 22

The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4184.6.

EXAMPLE 14 Preparation of Peptide Having SEQ ID NO. 23

The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4145.6.

EXAMPLE 15 Preparation of Peptide Having SEQ ID NO. 24

The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4224.7.

EXAMPLE 16 Preparation of Peptide Having SEQ ID NO. 25

The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4172.6.

EXAMPLE 17 Preparation of Peptide Having SEQ ID NO. 26

The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4115.5.

EXAMPLE 18 Preparation of Peptide Having SEQ ID NO. 27

The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4188.6.

EXAMPLE 19 Preparation of Peptide Having SEQ ID NO. 28

The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4131.6.

EXAMPLE 20 Preparation of Peptide Having SEQ ID NO. 29

The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4172.6.

EXAMPLE 21 Preparation of Peptide Having SEQ ID NO. 30

The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4145.6.

EXAMPLE 22 Preparation of Peptide Having SEQ ID NO. 31

The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Additional double couplings arerequired at the thioproline positions 38, 37, 36 and 31. Used inanalysis are Solvent A (0.1% TFA in water) and Solvent B (0.1% TFA inACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent Aover 30 minutes) of the lyophilized peptide is then carried out todetermine the retention time of the product peptide. Electrospray MassSpectrometry (M): calculated 4266.8.

EXAMPLE 23 Preparation of Peptide Having SEQ ID NO. 32

The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Additional double couplings arerequired at the thioproline positions 38, 37 and 36. Used in analysisare Solvent A (0.1% TFA in water) and Solvent B (0.1% TFA in ACN).Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent A over 30minutes) of the lyophilized peptide is then carried out to determine theretention time of the product peptide. Electrospray Mass Spectrometry(M): calculated 4246.8.

EXAMPLE 24 Preparation of Peptide Having SEQ ID NO. 33

The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Additional double couplings arerequired at the homoproline positions 38, 37, 36 and 31. Used inanalysis are Solvent A (0.1% TFA in water) and Solvent B (0.1% TFA inACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent Aover 30 minutes) of the lyophilized peptide is then carried out todetermine the retention time of the product peptide. Electrospray MassSpectrometry (M): calculated 4250.8.

EXAMPLE 25 Preparation of Peptide Having SEQ ID NO. 34

The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Additional double couplings arerequired at the homoproline positions 38, 37, and 36. Used in analysisare Solvent A (0.1% TFA in water) and Solvent B (0.1% TFA in ACN).Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent A over 30minutes) of the lyophilized peptide is then carried out to determine theretention time of the product peptide. Electrospray Mass Spectrometry(M): calculated 4234.8.

EXAMPLE 26 Preparation of Peptide Having SEQ ID NO. 35

The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Additional double couplings arerequired at the thioproline positions 38, 37, 36 and 31. Used inanalysis are Solvent A (0.1% TFA in water) and Solvent B (0.1% TFA inACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent Aover 30 minutes) of the lyophilized peptide is then carried out todetermine the retention time of the product peptide. Electrospray MassSpectrometry (M): calculated 4209.8.

EXAMPLE 27 Preparation of Peptide Having SEQ ID NO. 36

The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Additional double couplings arerequired at the homoproline positions 38, 37, 36 and 31. Used inanalysis are Solvent A (0.1% TFA in water) and Solvent B (0.1% TFA inACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent Aover 30 minutes) of the lyophilized peptide is then carried out todetermine the retention time of the product peptide. Electrospray MassSpectrometry (M): calculated 4193.7.

EXAMPLE 28 Preparation of Peptide Having SEQ ID NO. 37

The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Additional double couplings arerequired at the N-methylalanine positions 38, 37, 36 and 31. Used inanalysis are Solvent A (0.1% TFA in water) and Solvent B (0.1% TFA inACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent Aover 30 minutes) of the lyophilized peptide is then carried out todetermine the retention time of the product peptide. Electrospray MassSpectrometry (M): calculated 3858.2.

EXAMPLE 29 Preparation of Peptide Having SEQ ID NO. 38

The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Additional double couplings arerequired at the N-methylalanine positions 38, 37 and 36. Used inanalysis are Solvent A (0.1% TFA in water) and Solvent B (0.1% TFA inACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent Aover 30 minutes) of the lyophilized peptide is then carried out todetermine the retention time of the product peptide. Electrospray MassSpectrometry (M): calculated 3940.3.

EXAMPLE 30 Preparation of Peptide Having SEQ ID NO. 39

The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 1. Additional double couplings arerequired at the N-methylalanine positions 38, 37, 36 and 31. Used inanalysis are Solvent A (0.1% TFA in water) and Solvent B (0.1% TFA inACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent Aover 30 minutes) of the lyophilized peptide is then carried out todetermine the retention time of the product peptide. Electrospray MassSpectrometry (M): calculated 3801.1.

EXAMPLE 31 Preparation of C-Terminal Carboxylic Acid PeptidesCorresponding to the Above C-Terminal Amide Sequences

The above peptides of Examples 1-5 to 30 are assembled on the so calledWang resin (p-alkoxybenzylalacohol resin (Bachem, 0.54 mmole/g)) usingFmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from theresin, deprotected and purified in a similar way to Example 1. Used inanalysis are Solvent A (0.1% TFA in water) and Solvent B (0.1% TFA inACN). Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent Aover 30 minutes) of the lyophilized peptide is then carried out todetermine the retention time of the product peptide. Electrospray MassSpectrometry provides an experimentally determined (M).

EXAMPLE 32 Preparation of Peptide Having SEQ ID NO. 7

(SEQ ID NO. 7) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly-NH₂

The above amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.). In general, single-coupling cycles were usedthroughout the synthesis and Fast Moc (HBTU activation) chemistry wasemployed. Deprotection (Fmoc group removal) of the growing peptide chainwas achieved using piperidine. Final deprotection of the completedpeptide resin was achieved using a mixture of triethylsilane (0.2 mL),ethanedithiol (0.2 mL), anisole (0.2 mL), water (0.2 mL) andtrifluoroacetic acid (15 mL) according to standard methods (Introductionto Cleavage Techniques, Applied Biosystems, Inc.) The peptide wasprecipitated in ether/water (50 mL) and centrifuged. The precipitate wasreconstituted in glacial acetic acid and lyophilized. The lyophilizedpeptide was dissolved in water). Crude purity was about 75%.

Used in purification steps and analysis were Solvent A (0.1% TFA inwater) and Solvent B (0.1% TFA in ACN). The solution containing peptidewas applied to a preparative C-18 column and purified (10% to 40%Solvent B in Solvent A over 40 minutes). Purity of fractions wasdetermined isocratically using a C-18 analytical column. Pure fractionswere pooled furnishing the above-identified peptide. Analytical RP-HPLC(gradient 30% to 50% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 18.9 minutes. Electrospray Mass Spectrometry (M): calculated3408.0. found 3408.9.

EXAMPLE 33 Preparation of Peptide Having SEQ ID NO. 40

(SEQ ID NO. 40) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

The above amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 40% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 17.9 minutes. Electrospray Mass Spectrometry (M): calculated3294.7. found 3294.8.

EXAMPLE 34 Preparation of Peptide Having SEQ ID NO. 41

(SEQ ID NO. 41) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 29% to 36% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 20.7 minutes. Electrospray Mass Spectrometry (M): calculated3237.6. found 3240.

EXAMPLE 35 Preparation of Peptide Having SEQ ID NO. 42

(SEQ ID NO. 42) His Ala Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 36% to 46% Solvent P in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 15.2 minutes. Electrospray Mass Spectrometry (M): calculated3251.6. found 3251.5.

EXAMPLE 36 Preparation of Peptide Having SEQ ID NO. 43

(SEQ ID NO. 43) His Gly Glu Gly Ala Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 36% to 46% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 13.1 minutes. Electrospray Mass Spectrometry (M): calculated3207.6. found 3208.3.

EXAMPLE 37 Preparation of Peptide Having SEQ ID NO. 44

(SEQ ID NO. 44) His Gly Glu Gly Thr Ala Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 35% to 45% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 12.8 minutes. Electrospray Mass Spectrometry (M): calculated3161.5. found 3163.

EXAMPLE 38 Preparation of Peptide Having SEQ ID NO. 45

(SEQ ID NO. 45) His Gly Glu Gly Thr Phe Thr Ala Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 36% to 46% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 15.2 minutes. Electrospray Mass Spectrometry (M): calculated3221.6. found 3222.7.

EXAMPLE 39 Preparation of Peptide Having SEQ ID NO. 46

(SEQ ID NO. 46) His Gly Glu Gly Thr Phe Thr Ser Asp Ala Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 34% to 44% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 14.3 minutes. Electrospray Mass Spectrometry (M): calculated3195.5. found 3199.4.

EXAMPLE 40 Preparation of Peptide Having SEQ ID NO. 47

(SEQ ID NO. 47) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ala Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 38% to 48% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 15.7 minutes. Electrospray Mass Spectrometry (M): calculated3221.6. found 3221.6.

EXAMPLE 41 Preparation of Peptide Having SEQ ID NO. 48

(SEQ ID NO. 48) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Ala Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 38% to 48% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 18.1 minutes. Electrospray Mass Spectrometry (M): calculated3180.5. found 3180.9.

EXAMPLE 42 Preparation of Peptide Having SEQ ID NO. 49

(SEQ ID NO. 49) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Ala LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 36% to 46% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 17.0 minutes. Electrospray Mass Spectrometry (M): calculated3180.6. found 3182.8.

EXAMPLE 43 Preparation of Peptide Having SEQ ID NO. 50

(SEQ ID NO. 50) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln AlaGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 32% to 42% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 14.9 minutes. Electrospray Mass Spectrometry (M): calculated3195.5. found 3195.9.

EXAMPLE 44 Preparation of Peptide Having SEQ ID NO. 51

(SEQ ID NO. 51) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuAla Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 37% to 47% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 17.9 minutes. Electrospray Mass Spectrometry (M): calculated3179.6. found 3179.0.

EXAMPLE 45 Preparation of Peptide Having SEQ ID NO. 52

(SEQ ID NO. 52) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Ala Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 37% to 47% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 14.3 minutes. Electrospray Mass Spectrometry (M): calculated3179.6. found 3180.0.

EXAMPLE 46 Preparation of Peptide Having SEQ ID NO. 53

(SEQ ID NO. 53) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Ala Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 37% to 47% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 13.7 minutes. Electrospray Mass Spectrometry (M): calculated3179.6. found 3179.0.

EXAMPLE 47 Preparation of Peptide Having SEQ ID NO. 54

(SEQ ID NO. 54) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Ala Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 35% to 45% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 14.0 minutes. Electrospray Mass Spectrometry (M): calculated3209.6. found 3212.8.

EXAMPLE 48 Preparation of Peptide Having SEQ ID NO. 55

(SEQ ID NO. 55) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Ala Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 38% to 48% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 14.3 minutes. Electrospray Mass Spectrometry (M): calculated3152.5. found 3153.5.

EXAMPLE 49 Preparation of Peptide Having SEQ ID NO. 56

(SEQ ID NO. 56) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Ala Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 35% to 45% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 12.1 minutes. Electrospray Mass Spectrometry (M): calculated3195.5. found 3197.7.

EXAMPLE 50 Preparation of Peptide Having SEQ ID NO. 57

(SEQ ID NO. 57) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Ala Phe Leu Lys Asn-NH₂

The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 38% to 48% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 10.9 minutes. Electrospray Mass Spectrometry (M): calculated3179.6. found 3180.5.

EXAMPLE 51 Preparation of Peptide Having SEQ ID NO. 58

(SEQ ID NO. 58) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Ala Leu Lys Asn-NH₂

The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 32% to 42% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 17.5 minutes. Electrospray Mass Spectrometry (M): calculated3161.5. found 3163.0.

EXAMPLE 52 Preparation of Peptide Having SEQ ID NO. 59

(SEQ ID NO. 59) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Ala Lys Asn-NH₂

The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 32% to 42% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 19.5 minutes. Electrospray Mass Spectrometry (M): calculated3195.5. found 3199.

EXAMPLE 53 Preparation of Peptide Having SEQ ID NO. 60

(SEQ ID NO. 60) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Ala Asn-NH₂

The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 38% to 48% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 14.5 minutes. Electrospray Mass Spectrometry (M): calculated3180.5. found 3183.7.

EXAMPLE 54 Preparation of Peptide Having SEQ ID NO. 61

(SEQ ID NO. 61) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Ala-NH₂

The above-identified amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 34% to 44% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 22.8 minutes. Electrospray Mass Spectrometry (M): calculated3194.6. found 3197.6.

EXAMPLE 55 Preparation of Peptide Having SEQ ID NO. 62

(SEQ ID NO. 62) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro SerSer Gly Ala Pro Pro Pro-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4099.6.

EXAMPLE 56 Preparation of Peptide Having SEQ ID NO. 63

(SEQ ID NO. 63) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro SerSer Gly Ala Pro Pro Pro-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4042.5.

EXAMPLE 57 Preparation of Peptide Having SEQ ID NO. 64

(SEQ ID NO. 64) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro SerSer Gly Ala Pro Pro-NH₂

The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4002.4.

EXAMPLE 58 Preparation of Peptide Having SEQ ID NO. 65

(SEQ ID NO. 65) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro SerSer Gly Ala Pro Pro-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3945.4.

EXAMPLE 59 Preparation of Peptide Having SEQ ID NO. 66

(SEQ ID NO. 66) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro SerSer Gly Ala Pro-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3905.3.

EXAMPLE 60 Preparation of Peptide Having SEQ ID NO. 67

(SEQ ID NO. 67) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro SerSer Gly Ala Pro-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3848.2.

EXAMPLE 61 Preparation of Peptide Having SEQ ID NO. 68

(SEQ ID NO. 68) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro SerSer Gly Ala-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3808.2.

EXAMPLE 62 Preparation of Peptide Having SEQ ID NO. 69

(SEQ ID NO. 69) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro SerSer Gly Ala-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3751.1.

EXAMPLE 63 Preparation of Peptide Having SEQ ID NO. 70

(SEQ ID NO. 70) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro SerSer Gly-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3737.1.

EXAMPLE 64 Preparation of Peptide Having SEQ ID NO. 71

(SEQ ID NO. 71) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro SerSer Gly-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3680.1.

EXAMPLE 65 Preparation of Peptide Having SEQ ID NO. 72

(SEQ ID NO. 72) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro SerSer-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3680.1.

EXAMPLE 66 Preparation of Peptide Having SEQ ID NO. 73

(SEQ ID NO. 73) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro SerSer-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3623.0.

EXAMPLE 67 Preparation of Peptide Having SEQ ID NO. 74

(SEQ ID NO. 74) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly ProSer-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent P in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3593.0.

EXAMPLE 68 Preparation of Peptide Having SEQ ID NO. 75

(SEQ ID NO. 75) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly ProSer-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3535.9.

EXAMPLE 69 Preparation of Peptide Having SEQ ID NO. 76

(SEQ ID NO. 76) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro-NH₂

EXAMPLE 70 Preparation of Peptide Having SEQ ID NO. 77

(SEQ ID NO. 77) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3448.8.

EXAMPLE 71 Preparation of Peptide Having SEQ ID NO. 78

(SEQ ID NO. 78) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly-NH₂

The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3351.7.

EXAMPLE 72 Preparation of Peptide Having SEQ ID NO. 79

(SEQ ID NO. 79) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly-NH₂

The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3351.8.

EXAMPLE 73 Preparation of Peptide Having SEQ ID NO. 80

(SEQ ID NO. 80) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3294.7.

EXAMPLE 74 Preparation of Peptide Having SEQ ID NO. 81

(SEQ ID NO. 81) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly tPro SerSer Gly Ala tPro tPro tPro-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Double couplings are requiredat residues 37, 36 and 31. Used in analysis are Solvent A (0.1% TFA inwater) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 30%to 60% Solvent B in Solvent A over 30 minutes) of the lyophilizedpeptide is then carried out to determine the retention time of theproduct peptide. Electrospray Mass Spectrometry (M): calculated 4197.1.

EXAMPLE 75 Preparation of Peptide Having SEQ ID NO. 82

(SEQ ID NO. 82) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro SerSer Gly Ala tPro tPro tPro-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Double couplings are requiredat residues 37, 36 and 31. Used in analysis are Solvent A (0.1% TFA inwater) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 30%to 60% Solvent B in Solvent A over 30 minutes) of the lyophilizedpeptide is then carried out to determine the retention time of theproduct peptide. Electrospray Mass Spectrometry (M): calculated 4179.1.

EXAMPLE 76 Preparation of Peptide Having SEQ ID NO. 83

(SEQ ID NO. 83) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly NMealaSer Ser Gly Ala Pro Pro-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Double couplings are requiredat residues 36 and 31. Used in analysis are Solvent A (0.1% TFA inwater) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 30%to 60% Solvent B in Solvent A over 30 minutes) of the lyophilizedpeptide is then carried out to determine the retention time of theproduct peptide. Electrospray Mass Spectrometry (M): calculated 3948.3.

EXAMPLE 77 Preparation of Peptide Having SEQ ID NO. 84

(SEQ ID NO. 84 His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly NMeAlaSer Ser Gly Ala NMeala NMeAla-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Double couplings are requiredat residues 36 and 31. Used in analysis are Solvent A (0.1% TFA inwater) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 30%to 60% Solvent B in Solvent A over 30 minutes) of the lyophilizedpeptide is then carried out to determine the retention time of theproduct peptide. Electrospray Mass Spectrometry (M): calculated 3840.1.

EXAMPLE 78 Preparation of Peptide Having SEQ ID NO. 85

(SEQ ID NO. 85) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly hPro SerSer Gly Ala hPro hPro-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Double couplings are requiredat residues 36 and 31. Used in analysis are Solvent A (0.1% TFA inwater) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 30%to 60% Solvent B in Solvent A over 30 minutes) of the lyophilizedpeptide is then carried out to determine the retention time of theproduct peptide. Electrospray Mass Spectrometry (M): calculated 4050.1.

EXAMPLE 79 Preparation of Peptide Having SEQ ID NO. 86

(SEQ ID NO. 87) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly hPro SerSer Gly Ala hPro-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. A double coupling is requiredat residue 31. Used in analysis are Solvent A (0.1% TFA in water) andSolvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 30% to 60%Solvent B in Solvent A over 30 minutes) of the lyophilized peptide isthen carried out to determine the retention time of the product peptide.Electrospray Mass Spectrometry (M): calculated 3937.1.

EXAMPLE 80 Preparation of Peptide Having SEQ ID NO. 87

(SEQ ID NO. 87) Arg Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro SerSer Gly Ala-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3827.2.

EXAMPLE 81 Preparation of Peptide Having SEQ ID NO. 88

(SEQ ID NO. 88) His Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3394.8.

EXAMPLE 82 Preparation of Peptide Having SEQ ID NO. 89

(SEQ ID NO. 89) His Gly Glu Gly Thr NaphthylAla Thr Ser Asp Leu Ser LysGln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3289.5.

EXAMPLE 83 Preparation of Peptide Having SEQ ID NO. 90

(SEQ ID NO. 90) His Gly Glu Gly Thr Phe Ser Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3280.7.

EXAMPLE 84 Preparation of Peptide Having SEQ ID NO. 91

(SEQ ID NO. 91) His Gly Glu Gly Thr Phe Ser Thr Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3294.7.

EXAMPLE 85 Preparation of Peptide Having SEQ ID NO. 92

(SEQ ID NO. 92) His Gly Glu Gly Thr Phe Thr Ser Glu Leu Ser Lys Gln MetAla Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3250.7.

EXAMPLE 86 Preparation of Peptide Having SEQ ID NO. 93

(SEQ ID NO. 93) His Gly Glu Gly Thr Phe Thr Ser Asp pentylgly Ser LysGln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3253.5.

EXAMPLE 87 Preparation of Peptide Having SEQ ID NO. 94

(SEQ ID NO. 94) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu NaphthylAla Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN) Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3289.5.

EXAMPLE 88 Preparation of Peptide Having SEQ ID NO. 95

(SEQ ID NO. 95) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe tbutylGly Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3183.4.

EXAMPLE 89 Preparation of Peptide Having SEQ ID NO. 96

(SEQ ID NO. 96) His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Asp Phe Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3237.6.

EXAMPLE 90 Preparation of Peptide Having SEQ ID NO. 97

(SEQ ID NO. 97) His Gly Glu Gly Thr Phe Thr Ser Asp Ala Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro SerSer-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3637.9.

EXAMPLE 91 Preparation of Peptide Having SEQ ID NO. 98

(SEQ ID NO. 98) His Gly Glu Gly Thr Phe Thr Ser Asp Ala Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3309.7.

EXAMPLE 92 Preparation of Peptide Having SEQ ID NO. 99

(SEQ ID NO. 99) His Gly Glu Gly Thr Phe Thr Ser Asp Ala Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly hPro SerSer Gly Ala hPro hPro-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 37. Double couplings are requiredat residues 36 and 31. Used in analysis are Solvent A (0.1% TFA inwater) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 30%to 60% Solvent B in Solvent A over 30 minutes) of the lyophilizedpeptide is then carried out to determine the retention time of theproduct peptide. Electrospray Mass Spectrometry (M): calculated 3711.1.

EXAMPLE 93 Preparation of C-Terminal Carboxylic Acid PeptidesCorresponding to the Above C-Terminal Amide Sequences for SEQ ID NOs 7,40-61, 68-75, 78-80 and 87-96

Peptides having the sequences of SEQ ID NOs 7, 40-61, 68-75, 78-80 and87-96 are assembled on the so called Wang resin (p-alkoxybenzylalacoholresin (Bachem, 0.54 mmole/g)) using Fmoc-protected amino acids (AppliedBiosystems, Inc.), cleaved from the resin, deprotected and purified in asimilar way to Example 32. Used in analysis are Solvent A (0.1% TFA inwater) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 30%to 60% Solvent B in Solvent A over 30 minutes) of the lyophilizedpeptide is then carried out to determine the retention time of theproduct peptide. Electrospray Mass Spectrometry provides anexperimentally determined (M).

EXAMPLE 94 Preparation of C-Terminal Carboxylic Acid PeptidesCorresponding to the Above C-Terminal Amide Sequences for SEQ ID NOs62-67, 76, 77 and 81-86

Peptides having the sequences of SEQ ID NOs 62-67, 76, 77 and 81-86 areassembled on the 2-chlorotritylchloride resin (200-400 mesh), 2% DVB(Novabiochem, 0.4-1.0 mmole/g)) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 32. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry provides anexperimentally determined (M).

EXAMPLE 95 Preparation of Peptide Having SEQ ID NO. 100

(SEQ ID NO. 100) Ala Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.). In general, single-coupling cycles were usedthroughout the synthesis and Fast Moc (HBTU activation) chemistry wasemployed. Deprotection (Fmoc group removal) of the growing peptide chainwas achieved using piperidine. Final deprotection of the completedpeptide resin was achieved using a mixture of triethylsilane (0.2 mL),ethanedithiol (0.2 mL), anisole (0.2 mL), water (0.2 mL) andtrifluoroacetic acid (15 mL) according to standard methods (Introductionto Cleavage Techniques, Applied Biosystems, Inc.) The peptide wasprecipitated in ether/water (50 mL) and centrifuged. The precipitate wasreconstituted in glacial acetic acid and lyophilized. The lyophilizedpeptide was dissolved in water). Crude purity was about 75%.

Used in purification steps and analysis were Solvent A (0.1% TFA inwater) and Solvent B (0.1% TFA in ACN).

The solution containing peptide was applied to a preparative C-18 columnand purified (10% to 40% Solvent B in Solvent A over 40 minutes). Purityof fractions was determined isocratically using a C-18 analyticalcolumn. Pure fractions were pooled furnishing the above-identifiedpeptide. Analytical RP-HPLC (gradient 30% to 60% Solvent B in Solvent Aover 30 minutes) of the lyophilized peptide gave product peptide havingan observed retention time of 19.2 minutes. Electrospray MassSpectrometry (M): calculated 3171.6. found 3172.

EXAMPLE 96 Preparation of Peptide Having SEQ ID NO. 101

(SEQ ID NO. 101) His Gly Ala Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 36% to 46% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 14.9 minutes. Electrospray Mass Spectrometry (M): calculated3179.6. found 3180.

EXAMPLE 97 Preparation of Peptide Having SEQ ID NO. 102

(SEQ ID NO. 102) His Gly Glu Ala Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 37% to 47% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 12.2 minutes. Electrospray Mass Spectrometry (M): calculated3251.6. found 3253.3.

EXAMPLE 98 Preparation of Peptide Having SEQ ID NO. 103

(SEQ ID NO. 103) His Gly Glu Gly Thr Phe Thr Ser Ala Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above amidated peptide was assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis were Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 35% to 45% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide gave product peptide having an observed retentiontime of 16.3 minutes. Electrospray Mass Spectrometry (M): calculated3193.6. found 3197.

EXAMPLE 99 Preparation of Peptide Having SEQ ID NO. 104

(SEQ ID NO. 104) Ala Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3228.6.

EXAMPLE 100 Preparation of Peptide Having SEQ ID NO. 105

(SEQ ID NO. 105) His Gly Ala Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3234.7.

EXAMPLE 101 Preparation of Peptide Having SEQ ID NO. 106

(SEQ ID NO. 106) His Gly Glu Ala Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3308.7.

EXAMPLE 102 Preparation of Peptide Having SEQ ID NO. 107

(SEQ ID NO. 107) His Gly Glu Gly Thr Phe Thr Ser Ala Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3250.7.

EXAMPLE 103 Preparation of Peptide Having SEQ ID NO. 108

(SEQ ID NO. 108) His Gly Glu Gly Thr Phe Thr Ser Asp Ala Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3252.6.

EXAMPLE 104 Preparation of Peptide Having SEQ ID NO. 109

(SEQ ID NO. 109) Ala Ala Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(21-41-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3200.6.

EXAMPLE 105 Preparation of Peptide Having SEQ ID NO. 110

(SEQ ID NO. 110) Ala Ala Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3143.5.

EXAMPLE 106 Preparation of Peptide Having SEQ ID NO. 111

(SEQ ID NO. 111) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3214.6.

EXAMPLE 107 Preparation of Peptide Having SEQ ID NO. 112

(SEQ ID NO. 112) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3157.5.

EXAMPLE 108 Preparation of Peptide Having SEQ ID NO. 113

(SEQ ID NO. 113) Ala Gly Asp Gly Ala Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3184.6.

EXAMPLE 109 Preparation of Peptide Having SEQ ID NO. 114

(SEQ ID NO. 114) Ala Gly Asp Gly Ala Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3127.5.

EXAMPLE 110 Preparation of Peptide Having SEQ ID NO. 115

(SEQ ID NO. 115) Ala Gly Asp Gly Thr NaphthylAla Thr Ser Asp Leu Ser LysGln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3266.4.

EXAMPLE 111 Preparation of Peptide Having SEQ ID NO. 116

(SEQ ID NO. 116) Ala Gly Asp Gly Thr NaphthylAla Thr Ser Asp Leu Ser LysGln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3209.4.

EXAMPLE 112 Preparation of Peptide Having SEQ ID NO. 117

(SEQ ID NO. 117) Ala Gly Asp Gly Thr Phe Ser Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3200.6.

EXAMPLE 113 Preparation of Peptide Having SEQ ID NO. 118

(SEQ ID NO. 118) Ala Gly Asp Gly Thr Phe Ser Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3143.5.

EXAMPLE 114 Preparation of Peptide Having SEQ ID NO. 119

(SEQ ID NO. 119) Ala Gly Asp Gly Thr Phe Thr Ala Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3198.6.

EXAMPLE 115 Preparation of Peptide Having SEQ ID NO. 120

(SEQ ID NO. 120) Ala Gly Asp Gly Thr Phe Thr Ala Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3141.5.

EXAMPLE 116 Preparation of Peptide Having SEQ ID NO. 121

(SEQ ID NO. 121) Ala Gly Asp Gly Thr Phe Thr Ser Ala Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

The above-identified peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3170.6.

EXAMPLE 117 Preparation of Peptide Having SEQ ID NO. 122

(SEQ ID NO. 122) Ala Gly Asp Gly Thr Phe Thr Ser Ala Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3113.5.

EXAMPLE 118 Preparation of Peptide Having SEQ ID NO. 123

(SEQ ID NO. 123) Ala Gly Asp Gly Thr Phe Thr Ser Glu Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3228.6.

EXAMPLE 119 Preparation of Peptide Having SEQ ID NO. 124

(SEQ ID NO. 124) Ala Gly Asp Gly Thr Phe Thr Ser Glu Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3171.6.

EXAMPLE 120 Preparation of Peptide Having SEQ ID NO. 125

(SEQ ID NO. 125) Ala Gly Asp Gly Thr Phe Thr Ser Asp Ala Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3172.5.

EXAMPLE 121 Preparation of Peptide Having SEQ ID NO. 126

(SEQ ID NO. 126) Ala Gly Asp Gly Thr Phe Thr Ser Asp Ala Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3115.4.

EXAMPLE 122 Preparation of Peptide Having SEQ ID NO. 127

(SEQ ID NO. 127) Ala Gly Asp Gly Thr Phe Thr Ser Asp pentylGly Ser LysGln Met Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3230.4.

EXAMPLE 123 Preparation of Peptide Having SEQ ID NO. 128

(SEQ ID NO. 128) Ala Gly Asp Gly Thr Phe Thr Ser Asp pentylGly Ser LysGln Leu Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3198.6.

EXAMPLE 124 Preparation of Peptide Having SEQ ID NO. 129

(SEQ ID NO. 129) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ala Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3141.5.

EXAMPLE 125 Preparation of Peptide Having SEQ ID NO. 130

(SEQ ID NO. 130) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ala Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3157.5.

EXAMPLE 126 Preparation of Peptide Having SEQ ID NO. 131

(SEQ ID NO. 131) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Ala Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3100.4.

EXAMPLE 127 Preparation of Peptide Having SEQ ID NO. 132

(SEQ ID NO. 132) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Ala Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3157.6.

EXAMPLE 128 Preparation of Peptide Having SEQ ID NO. 133

(SEQ ID NO. 133) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Ala MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3100.5.

EXAMPLE 129 Preparation of Peptide Having SEQ ID NO. 134

(SEQ ID NO. 134) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Ala LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3100.5.

EXAMPLE 130 Preparation of Peptide Having SEQ ID NO. 135

(SEQ ID NO. 135) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln AlaGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3154.5.

EXAMPLE 131 Preparation of Peptide Having SEQ ID NO. 136

(SEQ ID NO. 136) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln AlaGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3115.5.

EXAMPLE 132 Preparation of Peptide Having SEQ ID NO. 137

(SEQ ID NO. 137) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnpentylGly Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3212.4.

EXAMPLE 133 Preparation of Peptide Having SEQ ID NO. 138

(SEQ ID NO. 138) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys GlnpentylGly Glu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3173.4.

EXAMPLE 134 Preparation of Peptide Having SEQ ID NO. 139

(SEQ ID NO. 139) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetAla Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3156.6.

EXAMPLE 135 Preparation of Peptide Having SEQ ID NO. 140

(SEQ ID NO. 140) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuAla Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3099.5.

EXAMPLE 136 Preparation of Peptide Having SEQ ID NO. 141

(SEQ ID NO. 141) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Ala Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3156.6.

EXAMPLE 137 Preparation of Peptide Having SEQ ID NO. 142

(SEQ ID NO. 142) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Ala Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/9) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3099.5.

EXAMPLE 138 Preparation of Peptide Having SEQ ID NO. 143

(SEQ ID NO. 143) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Ala Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3156.6.

EXAMPLE 139 Preparation of Peptide Having SEQ ID NO. 144

(SEQ ID NO. 144) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Ala Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3099.5.

EXAMPLE 140 Preparation of Peptide Having SEQ ID NO. 145

(SEQ ID NO. 145) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Ala Arg Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3186.6.

EXAMPLE 141 Preparation of Peptide Having SEQ ID NO. 146

(SEQ ID NO. 146) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Ala Arg Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3129.5.

EXAMPLE 142 Preparation of Peptide Having SEQ ID NO. 147

(SEQ ID NO. 147) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Ala Leu Phe Ile Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3129.5.

EXAMPLE 143 Preparation of Peptide Having SEQ ID NO. 148

(SEQ ID NO. 148) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Ala Leu Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3072.4.

EXAMPLE 144 Preparation of Peptide Having SEQ ID NO. 149

(SEQ ID NO. 149) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Ala Phe Ile Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3172.5.

EXAMPLE 145 Preparation of Peptide Having SEQ ID NO. 150

(SEQ ID NO. 150) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Ala Phe Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3115.5.

EXAMPLE 146 Preparation of Peptide Having SEQ ID NO. 151

(SEQ ID NO. 151) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu naphthylAla Ile Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using, Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3266.4.

EXAMPLE 147 Preparation of Peptide Having SEQ ID NO. 152

(SEQ ID NO. 152) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu naphthylAla Ile Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3209.4.

EXAMPLE 148 Preparation of Peptide Having SEQ ID NO. 153

(SEQ ID NO. 153) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Val Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3200.6.

EXAMPLE 149 Preparation of Peptide Having SEQ ID NO. 154

(SEQ ID NO. 154) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Val Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3143.5.

EXAMPLE 150 Preparation of Peptide Having SEQ ID NO. 155

(SEQ ID NO. 155) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe tbutylGly Glu Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3216.5.

EXAMPLE 151 Preparation of Peptide Having SEQ ID NO. 156

(SEQ ID NO. 156) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe tbutylGly Glu Phe Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3159.4.

EXAMPLE 152 Preparation of Peptide Having SEQ ID NO. 157

(SEQ ID NO. 157) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Asp Trp Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3200.6.

EXAMPLE 153 Preparation of Peptide Having SEQ ID NO. 158

(SEQ ID NO. 158) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Asp Phe Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3143.5.

EXAMPLE 154 Preparation of Peptide Having SEQ ID NO. 159

(SEQ ID NO. 159) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Ala Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3099.5.

EXAMPLE 155 Preparation of Peptide Having SEQ ID NO. 160

(SEQ ID NO. 160) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Ala Leu Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3081.4.

EXAMPLE 156 Preparation of Peptide Having SEQ ID NO. 161

(SEQ ID NO. 161) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Ala Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3172.5.

EXAMPLE 157 Preparation of Peptide Having SEQ ID NO. 162

(SEQ ID NO. 162) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Ala Lys Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3115.5.

EXAMPLE 158 Preparation of Peptide Having SEQ ID NO. 163

(SEQ ID NO. 163) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Ala Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3157.5.

EXAMPLE 159 Preparation of Peptide Having SEQ ID NO. 164

(SEQ ID NO. 164) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Ala Asn-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3100.4.

EXAMPLE 160 Preparation of Peptide Having SEQ ID NO. 165

(SEQ ID NO. 165) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Ala-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3171.6.

EXAMPLE 161 Preparation of Peptide Having SEQ ID NO. 166

(SEQ ID NO. 166) Ala Gly Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Ala-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3114.5.

EXAMPLE 162 Preparation of Peptide Having SEQ ID NO. 167

(SEQ ID NO. 167) Ala Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro SerSer Gly Ala Pro Pro Pro-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4033.5.

EXAMPLE 163 Preparation of Peptide Having SEQ ID NO. 168

(SEQ ID NO. 168) His Gly Ala Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro SerSer Gly Ala Pro Pro Pro-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3984.4.

EXAMPLE 164 Preparation of Peptide Having SEQ ID NO. 169

(SEQ ID NO. 169) His Gly Glu Ala Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro SerSer Gly Ala Pro Pro-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4016.5.

EXAMPLE 165 Preparation of Peptide Having SEQ ID NO. 170

(SEQ ID NO. 170) His Gly Glu Gly Thr Phe Thr Ser Ala Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro SerSer Gly Ala Pro-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3861.3.

EXAMPLE 166 Preparation of Peptide Having SEQ ID NO. 171

(SEQ ID NO. 171) Ala Gly Glu Gly Thr Phe Thr Ser Asp Ala Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro SerSer Gly Ala Pro-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3746.1.

EXAMPLE 167 Preparation of Peptide Having SEQ ID NO. 172

(SEQ ID NO. 172) Ala Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro SerSer Gly Ala-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3742.1.

EXAMPLE 168 Preparation of Peptide Having SEQ ID NO. 173

(SEQ ID NO. 173) His Gly Ala Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro SerSer Gly Ala-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3693.1.

EXAMPLE 169 Preparation of Peptide Having SEQ ID NO. 174

(SEQ ID NO. 174) His Gly Glu Ala Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro SerSer Gly-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3751.2.

EXAMPLE 170 Preparation of Peptide Having SEQ ID NO. 175

(SEQ ID NO. 175) His Gly Glu Gly Thr Phe Thr Ser Ala Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro SerSer-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3634.1.

EXAMPLE 171 Preparation of Peptide Having SEQ ID NO. 176

(SEQ ID NO. 176) Ala Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly ProSer-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3526.9.

EXAMPLE 172 Preparation of Peptide Having SEQ ID NO. 177

(SEQ ID NO. 177) His Gly Ala Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly ProSer-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3477.9.

EXAMPLE 173 Preparation of Peptide Having SEQ ID NO. 178

(SEQ ID NO. 178) His Gly Glu Ala Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3519.9.

EXAMPLE 174 Preparation of Peptide Having SEQ ID NO. 179

(SEQ ID NO. 179) His Gly Glu Gly Thr Phe Thr Ser Ala Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3307.7.

EXAMPLE 175 Preparation of Peptide Having SEQ ID NO. 180

(SEQ ID NO. 180) Ala Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3186.5.

EXAMPLE 176 Preparation of Peptide Having SEQ ID NO. 181

(SEQ ID NO. 181) His Gly Ala Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly tPro SerSer Gly Ala tPro tPro tPro-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Double couplings are requiredat residues 37, 36 and 31. Used in analysis are Solvent A (0.1% TFA inwater) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 30%to 60% Solvent B in Solvent A over 30 minutes) of the lyophilizedpeptide is then carried out to determine the retention time of theproduct peptide. Electrospray Mass Spectrometry (M): calculated 4121.1.

EXAMPLE 177 Preparation of Peptide Having SEQ ID NO. 182

(SEQ ID NO. 182) His Gly Glu Ala Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro SerSer Gly Ala tPro tPro tPro-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Double couplings are requiredat residues 37, 36 and 31. Used in analysis are Solvent A (0.1% TFA inwater) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 30%to 60% Solvent B in Solvent A over 30 minutes) of the lyophilizedpeptide is then carried out to determine the retention time of theproduct peptide. Electrospray Mass Spectrometry (M): calculated 4173.2.

EXAMPLE 178 Preparation of Peptide Having SEQ ID NO. 183

(SEQ ID NO. 183) His Gly Glu Gly Thr Phe Thr Ser Ala Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly NMeAlaSer Ser Gly Ala NMeAla NMeAla-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Compound 1. Double couplings are requiredat residues 36 and 31. Used in analysis are Solvent A (0.1% TFA inwater) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 30%to 60% Solvent B in Solvent A over 30 minutes) of the lyophilizedpeptide is then carried out to determine the retention time of theproduct peptide. Electrospray Mass Spectrometry (M): calculated 3796.1.

EXAMPLE 179 Preparation of Peptide Having SEQ ID NO. 184

(SEQ ID NO. 184) Ala Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly hPro SerSer Gly Ala hPro-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. A double coupling is requiredat residue 31. Used in analysis are Solvent A (0.1% TFA in water) andSolvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 30% to 60%Solvent B in Solvent A over 30 minutes) of the lyophilized peptide isthen carried out to determine the retention time of the product peptide.Electrospray Mass Spectrometry (M): calculated 3871.1.

EXAMPLE 180 Preparation of Peptide Having SEQ ID NO. 185

(SEQ ID NO. 185) His Gly Ala Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro SerSer Gly Ala-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3750.2.

EXAMPLE 181 Preparation of Peptide Having SEQ ID NO. 186

(SEQ ID NO. 186) His Gly Asp Ala Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated3408.8.

EXAMPLE 182 Preparation of Peptide Having SEQ ID NO. 187

(SEQ ID NO. 187) Ala Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln MetGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro SerSer Gly Ala Pro Pro Pro Ser-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4120.6.

EXAMPLE 183 Preparation of Peptide Having SEQ ID NO. 188

(SEQ ID NO. 188) Ala Gly Ala Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln LeuGlu Glu Glu Ala Val Arg Leu Phe Ile Glu Phe Leu Lys Asn Gly Gly Pro SerSer Gly Ala Pro Pro Pro Ser-NH₂

The above-identified amidated peptide is assembled on4-(2′-4′-dimethoxyphenyl)-Fmoc aminomethyl phenoxy acetamide norleucineMBHA resin (Novabiochem, 0.55 mmole/g) using Fmoc-protected amino acids(Applied Biosystems, Inc.), cleaved from the resin, deprotected andpurified in a similar way to Example 95. Used in analysis are Solvent A(0.1% TFA in water) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC(gradient 30% to 60% Solvent B in Solvent A over 30 minutes) of thelyophilized peptide is then carried out to determine the retention timeof the product peptide. Electrospray Mass Spectrometry (M): calculated4005.5.

EXAMPLE 184 Preparation of C-Terminal Carboxylic Acid PeptidesCorresponding to the Above C-Terminal Amide Sequences for PeptidesHaving SEQ ID NOs 100-166, 172-177, 179-180 and 185-188

C-terminal carboxylic acid peptides corresponding to amidated having SEQID NOs 100-166, 172-177, 179-180 and 185-188 are assembled on the socalled Wang resin (p-alkoxybenzylalacohol resin (Bachem, 0.54 mmole/g))using Fmoc-protected amino acids (Applied Biosystems, Inc.), cleavedfrom the resin, deprotected and purified in a similar way to thatdescribed in Example 95. Used in analysis are Solvent A (0.1% TFA inwater) and Solvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 30%to 60% Solvent B in Solvent A over 30 minutes) of the lyophilizedpeptide is then carried out to determine the retention time of theproduct peptide. Electrospray Mass Spectrometry provides anexperimentally determined (M).

EXAMPLE 185 Preparation of C-Terminal Carboxylic Acid PeptidesCorresponding to the Above C-Terminal Amide Sequences for PeptidesHaving SEQ ID NOs 167-171, 178 and 181-184

C-terminal carboxylic acid peptides corresponding to amidated SEQ ID NOs167-171, 178 and 181-184 are assembled on the 2-chlorotritylchlorideresin (200-400 mesh), 2% DVB (Novabiochem, 0.4-1.0 mmole/g)) usingFmoc-protected amino acids (Applied Biosystems, Inc.), cleaved from theresin, deprotected and purified in a similar way to that described inExample 95. Used in analysis are Solvent A (0.1% TFA in water) andSolvent B (0.1% TFA in ACN). Analytical RP-HPLC (gradient 30% to 60%Solvent B in Solvent A over 30 minutes) of the lyophilized peptide isthen carried out to determine the retention time of the product peptide.Electrospray Mass Spectrometry provides an experimentally determined(M).

EXAMPLE 186 Evaluation of Ability to Cross Placenta

I. Introduction

The purpose of this experiment was to determine whether this exendin-4,when delivered to the maternal circulation, is transported across theplacenta and is detectable in amniotic fluid or fetal blood.

II. Materials and Methods

Animals

Female Harlan Sprague Dawley rats (age 12 weeks, 17-21 days pregnant,approximately 300 grams) were housed at 22.8±0.8° C. in a 12:12 hourlight:dark cycle. All experiments were performed during the light cycle.Animals were given free access to food and water until the start of theexperiment.

Sample Collection

Rats were anesthetized with 5% halothane and then maintained with 2%halothane during the surgical procedures. Body temperature was measuredand controlled using a thermistor probe/controller (Model 73A, YSI,Yellow Springs, Ohio) and a heated operating table. Blood was collectedfrom the tail vein immediately prior to a subcutaneous injection ofexendin-4 (AC2993 Amylin Pharmaceuticals, Inc.) or vehicle (100 μl 0.15MNaCl) at t=0. At t=30 minutes, when plasma concentrations following asubcutaneous injection have been found to be maximal, another bloodsample was taken. Immediately thereafter, a midline laparotomy was madeto expose the uterine horns. Fluid was collected from the individualamniotic sacs by aspiration through a 16 g needle into a syringe. Theamniotic fluids from individual fetuses were pooled from a given rat,but fluids from each rat were kept separate. Fetal blood was collectedby heart puncture with a 28 g microfine needle and aspirated into asyringe. Amniotic fluid and fetal blood samples were collected within 10minutes of when the laparotomy was made (t=30-40 min.). All blood andfluid samples were centrifuged. The plasma or supernatant was stored at−70° C. until assayed.

Treatment Groups

There were 2 treatment groups: Group A: Rats receiving exendin-4dissolved at 21 μg/100 μl in 0.15M NaCl n=4. Group B: Rats receivingexendin-4 dissolved at 210 μg/100 μl in 0.15M NaCl n=5.

III. Results

Exendin-4 was not detected in any of the baseline samples, taken at t=0,when measured by a specific IRMA (immuno-radio-metric-assay) which has aLLQ (low limit of quantitation) of 15 pM. At t=30 plasma levels ofexendin-4 in the mother rats that received 21 μg exendin-4 were 16.47nM±2.45. Values obtained from amniotic fluid (6.1.+−.5.3 μM) and fetalblood (12.7±6.5 μM) were 2700-fold and 1300-fold less than those inplasma and were generally below the lower limit of quantitation of theassay (FIG. 2). Similar results were obtained with the rats receiving210 μg exendin-4 where plasma levels in the mother rats at t=30 were232.16 nM±63.45 (FIG. 3). Values obtained from amniotic fluid (18.3±9.3μM) and fetal blood (16.9×13.8 μM) were 12.680-fold and 13.750-fold lessthan those in plasma and were undetectable in over half of the samples.

IV. Discussion

The placenta is the organ responsible for nutrient and waste exchangebetween the fetus and the mother. Maternal and fetal circulations areseparated by an epithelial layer that allows or denies diffusion orcarrier mediated transport of substances across the interface. The riskof adverse effects on the fetus can be related to the extent to whichthe drug enters the fetal circulation. The data obtained here indicatethat, even with high injected doses, which may exceed the per-kilogramdoses administered to humans by up to 3000-fold, little or no exendin-4appeared in the fetal circulation or amniotic fluid. Six out of 15measurements were above the lower limit of quantitation, and in 9 of 15,exendin-4 was undetectable. In those samples in which exendin-4 wasmeasurable, its presence may have been due to contamination frommaternal blood (which need be present only at 1:1,000-1:10,000 to bemeasurable). Such contamination is possible following laparotomy of thedam and puncture of the fetus.

Various modifications of the invention in addition to those shown anddescribed herein will become apparent to those skilled in the art fromthe foregoing description and fall within the scope of the followingclaims.

1-33. (canceled)
 34. A method for treating gestational diabetes mellitusin a subject in need thereof comprising administering to the subject atherapeutically effective amount of an exendin peptide or an exendinagonist peptide to treat the gestational diabetes mellitus.
 35. Themethod of claim 34, wherein the exendin peptide or exendin agonistpeptide is administered continuously to the subject.
 36. The method ofclaim 34, wherein the exendin peptide or exendin agonist peptide isadministered to the subject by injection.
 37. The method of claim 34,wherein the exendin peptide or exendin agonist peptide is administeredto the subject by subcutaneous injection.
 38. The method of claim 34,wherein the therapeutically effective amount is 1 μg to 500 μg per day.39. The method of claim 34, wherein the therapeutically effective amountis 1 μg to 100 μg per day.
 40. The method of claim 34, wherein thetherapeutically effective amount is 1 μg to 50 μg per day.
 41. Themethod of claim 34, wherein the exendin peptide or exendin agonistpeptide is an exendin-3 peptide or an exendin-4 peptide.
 42. The methodof claim 34, wherein the exendin peptide or exendin agonist peptidecomprises an amino acid sequence of SEQ ID NO. 1, 2, 6, 7, 8, 9, 40, or41.
 43. The method of claim 34, wherein the exendin peptide or exendinagonist peptide comprises an amino acid sequence of SEQ ID NO. 3:Xaa₁ Xaa₂ Xaa₃ Gly Thr Xaa₄ Xaa₅ Xaa₆ Xaa₇ Xaa₈ Ser Lys Gln Xaa₉ Glu GluGlu Ala Val Arg Leu Xaa₁₀ Xaa₁₁ Xaa₁₂ Xaa₁₃ Leu Lys Asn Gly GlyXaa₁₄ Ser Ser Gly Ala Xaa₁₅ Xaa₁₆ Xaa₁₇ Xaa₁₈-Z;

wherein: Xaa₁ is His, Arg or Tyr; Xaa₂ is Ser, Gly, Ala or Thr; Xaa₃ isAsp or Glu; Xaa₄ is Phe, Tyr or naphthylalanine; Xaa₅ is Thr or Ser;Xaa₆ is Ser or Thr; Xaa₇ is Asp or Glu Xaa₈ is Leu, Ile, Val,pentylglycine or Met; Xaa₉ is Leu, Ile, pentylglycine, Val or Met; Xaa₁₀is Phe, Tyr or naphthylalanine; Xaa₁₁ is Ile, Val, Leu, pentylglycine,tert-butylglycine or Met; Xaa₁₂ is Glu or Asp; Xaa₁₃ is Trp, Phe, Tyr,or naphthylalanine; Xaa₁₄, Xaa₁₅, Xaa₁₆ and Xaa₁₇ are independently Pro,homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine,N-alkylpentylglycine or N-alkylalanine Xaa₁₈ is Ser, Thr or Try; and Zis —OH or —NH₂.
 44. A method for treating gestational diabetes mellitusin a subject in need thereof comprising administering to the subject apeptide comprising the amino acid sequence of SEQ ID NO. 2 in an amountof 1 μg to 100 μg per day to treat the gestational diabetes mellitus.45. The method of claim 44, wherein the exendin peptide or exendinagonist peptide is administered to the subject by injection.
 46. Themethod of claim 44, wherein the exendin peptide or exendin agonistpeptide is administered to the subject by subcutaneous injection. 47.The method of claim 44, wherein the peptide is administered in an amountof 1 μg to 50 μg per day.
 48. The method of claim 44, further comprisingadministering an insulin, an amylin agonist peptide, or a combinationthereof.
 49. A method for treating gestational diabetes mellitus in asubject in need thereof comprising administering to the subject atherapeutically effective amount of a peptide comprising the amino acidsequence of SEQ ID NO. 4 to treat the gestational diabetes mellitus;wherein SEQ ID NO. 4 is: Xaa₁ Xaa₂ Xaa₃ GlyXaa₅ Xaa₆ Xaa₇ Xaa₈ Xaa₉ Xaa₁₀Xaa₁₁ Xaa₁₂ Xaa₁₃ Xaa₁₄ Xaa₁₅ Xaa₁₆ Xaa₁₇ AlaXaa₁₉ Xaa₂₀ Xaa₂₁ Xaa₂₂ Xaa₂₃ Xaa₂₄ Xaa₂₅ Xaa₂₆ Xaa₂₇ Xaa₂₈-Z₁;

wherein: Xaa₁ is His, Arg or Tyr; Xaa₂ is Ser, Gly, Ala or Thr; Xaa₃ isAsp or Glu; Xaa₅ is Ala or Thr; Xaa₆ is Ala, Phe, Tyr ornaphthylalanine; Xaa₇ is Thr or Ser; Xaa₈ is Ala, Ser or Thr; Xaa₉ isAsp or Glu; Xaa₁₀ is Ala, Leu, Ile, Val, pentylglycine or Met; Xaa₁₁ isAla or Ser; Xaa₁₂ is Ala or Lys; Xaa₁₃ is Ala or Gln; Xaa₁₄ is Ala, Leu,Ile, pentylglycine, Val or Met; Xaa₁₅ is Ala or Glu; Xaa₁₆ is Ala orGlu; Xaa₁₇ is Ala or Glu; Xaa₁₈ is Ala or Val; Xaa₂₀ is Ala or Arg;Xaa₂₁ is Ala or Leu; Xaa₂₂ is Ala, Phe, Tyr or naphthylalanine; Xaa₂₃ isIle, Val, Leu, pentylglycine, tert-butylglycinc or Met; Xaa₂₄ is Ala,Glu or Asp; Xaa₂₅ is Ala, Trp, Phe, Tyr or naphthylalanine; Xaa₂₆ is Alaor Leu; Xaa₂₇ is Ala or Lys; Xaa₂₈ is Ala or Asn; Z₁ is OH, NH₂, Gly-Z₂,Gly Gly-Z₂, Gly Gly Xaa31-Z₂, Gly Gly Xaa₃₁ Ser-Z₂, Gly Gly Xaa₃₁ SerSer-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly Ala-Z₂,Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆-Z₂, Gly Gly Xaa₃₁ Ser Ser Gly AlaXaa₃₆ Xaa₃₇-Z₂, or Gly Gly Xaa₃₁ Ser Ser Gly Ala Xaa₃₆ Xaa₃₇ Xaa₃₈-Z₂;

Xaa₃₁, Xaa₃₆, Xaa₃₇ and Xaa₃₈ are independently Pro, homoproline, 3Hyp,4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine orN-alkylalanine; and Z₂ is —OH or —NH₂; provided that no more than threeof Xaa₃, Xaa₅, Xaa₆, Xaa₈, Xaa₁₀, Xaa₁₁, Xaa₁₂, Xaa₁₃, Xaa₁₄, Xaa₁₅,Xaa₁₆, Xaa₁₇, Xaa₁₈, Xaa₂₀, Xaa₂₁, Xaa₂₄, Xaa₂₅, Xaa₂₆, Xaa₂₇ and Xaa₂₈are Ala.
 50. The method of claim 49, wherein the exendin peptide orexendin agonist peptide is administered to the subject by subcutaneousinjection.
 51. The method of claim 49, wherein the therapeuticallyeffective amount is 1 μg to 100 μg per day.
 52. The method of claim 49,wherein the therapeutically effective amount is 1 μg to 50 μg per day.53. The method of claim 49, further comprising administering an insulin,an amylin agonist peptide, or a combination thereof.